17-31226455-C-T

Position:

chr17-31226455-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001042492.3(NF1):c.2022C>T(p.Ser674Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,546 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 26 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 18 hom. )

Consequence

NF1
NM_001042492.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -1.69

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 17-31226455-C-T is Benign according to our data. Variant chr17-31226455-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 141819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31226455-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.69 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00837 (1272/152040) while in subpopulation AFR AF= 0.0293 (1213/41446). AF 95% confidence interval is 0.0279. There are 26 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.2022C>T	p.Ser674Ser	synonymous_variant	18/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.2022C>T	p.Ser674Ser	synonymous_variant	18/57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.2022C>T	p.Ser674Ser	synonymous_variant	18/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00833

AC:

1265

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00213

AC:

534

AN:

250492

Hom.:

AF XY:

0.00162

AC XY:

219

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000948

AC:

1386

AN:

1461506

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

583

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0322

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000630

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

AF:

0.00837

AC:

1272

AN:

152040

Hom.:

Cov.:

AF XY:

0.00821

AC XY:

610

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0293

Gnomad4 AMR

AF:

0.00269

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00437

Hom.:

Bravo

AF:

0.00939

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser674Ser in exon 18 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 2.6% (113/4406) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230851). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 23, 2017	Variant summary: The NF1 c.2022C>T (p.Ser674Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 757/250454 control chromosomes (gnomAD) at a frequency of 0.0030225, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2016	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. -

Neurofibromatosis, type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2014	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 17, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

Neurofibromatosis, familial spinal

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.9

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over