NM_001042492.3:c.168C>T

Variant names:

• chr17-31156090-C-T
• rs17881168
• NM_001042492.3:c.168C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001042492.3(NF1):​c.168C>T​(p.Ser56Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,613,212 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.020 (311 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -0.416
• Publications: 16 publications found

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-31156090-C-T is Benign according to our data. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156090-C-T is described in CliVar as Benign. Clinvar id is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.416 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2004/151898) while in subpopulation NFE AF = 0.0232 (1576/67962). AF 95% confidence interval is 0.0222. There are 17 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2004 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.168C>T	p.Ser56Ser	synonymous_variant	Exon 2 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.168C>T	p.Ser56Ser	synonymous_variant	Exon 2 of 57		NP_000258.1
NF1	NM_001128147.3	c.168C>T	p.Ser56Ser	synonymous_variant	Exon 2 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.168C>T	p.Ser56Ser	synonymous_variant	Exon 2 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2003 AN: 151780 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00424

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00643

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00478

Gnomad FIN AF: 0.00832

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.0120 AC: 3002 AN: 251200 AF XY: 0.0119

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0198 AC: 28900 AN: 1461314 Hom.: 311 Cov.: 33 AF XY: 0.0193 AC XY: 14003 AN XY: 726964

African (AFR) AF: 0.00308 AC: 103 AN: 33460

American (AMR) AF: 0.00601 AC: 269 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 181 AN: 26122

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39604

South Asian (SAS) AF: 0.00554 AC: 478 AN: 86240

European-Finnish (FIN) AF: 0.0106 AC: 564 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0237 AC: 26290 AN: 1111618

Other (OTH) AF: 0.0165 AC: 999 AN: 60372

GnomAD4 genome AF: 0.0132 AC: 2004 AN: 151898 Hom.: 17 Cov.: 32 AF XY: 0.0120 AC XY: 888 AN XY: 74212

African (AFR) AF: 0.00422 AC: 175 AN: 41438

American (AMR) AF: 0.00642 AC: 98 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4810

European-Finnish (FIN) AF: 0.00832 AC: 87 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1576 AN: 67962

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0185 Hom.: 17

Bravo AF: 0.0127

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0216

EpiControl AF: 0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Nov 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser56Ser in exon 2 of NF1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 2% (180/8598) of Euro pean American chromosomes and 0.4% (16/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 7881168). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neurofibromatosis, type 1 Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Aug 31, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NF1 c.168C>T (p.Ser56Ser) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and ESE finder predicts the loss of ESE binding sites. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1449/121304 (1/83, 14 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic NF1 variant of 1/4798, suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "benign." Therefore, the variant of interest is classified as Benign. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurofibromatosis, familial spinal Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Benign:1

Jul 26, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis-Noonan syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Café-au-lait macules with pulmonary stenosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Mar 17, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome Benign:1

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.9
DANN	Benign	0.70
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17881168; hg19: chr17-29483108; COSMIC: COSV62213488;