17-31214419-T-C

Variant names:

• chr17-31214419-T-C
• rs2905876
• NM_001042492.3:c.1393-32T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.1393-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,535,034 control chromosomes in the GnomAD database, including 340,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25785 hom., cov: 31)
  • Exomes 𝑓: 0.67 (314788 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.807
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-31214419-T-C is Benign according to our data. Variant chr17-31214419-T-C is described in ClinVar as Benign. ClinVar VariationId is 257276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1393-32T>C		intron_variant	Intron 12 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.1393-32T>C		intron_variant	Intron 12 of 56		NP_000258.1
NF1	NM_001128147.3	c.1393-32T>C		intron_variant	Intron 12 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1393-32T>C		intron_variant	Intron 12 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81601 AN: 151806 Hom.: 25794 Cov.: 31

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.620 AC: 149631 AN: 241458 AF XY: 0.636

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 0.559

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.668

GnomAD4 exome AF: 0.667 AC: 922993 AN: 1383112 Hom.: 314788 Cov.: 23 AF XY: 0.670 AC XY: 463309 AN XY: 691984

African (AFR) AF: 0.166 AC: 5330 AN: 32072

American (AMR) AF: 0.509 AC: 22061 AN: 43304

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 19674 AN: 25412

East Asian (EAS) AF: 0.555 AC: 21733 AN: 39166

South Asian (SAS) AF: 0.635 AC: 52943 AN: 83370

European-Finnish (FIN) AF: 0.656 AC: 34838 AN: 53076

Middle Eastern (MID) AF: 0.743 AC: 2947 AN: 3964

European-Non Finnish (NFE) AF: 0.694 AC: 725588 AN: 1045134

Other (OTH) AF: 0.657 AC: 37879 AN: 57614

GnomAD4 genome AF: 0.537 AC: 81585 AN: 151922 Hom.: 25785 Cov.: 31 AF XY: 0.534 AC XY: 39676 AN XY: 74248

African (AFR) AF: 0.186 AC: 7729 AN: 41496

American (AMR) AF: 0.552 AC: 8425 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2663 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2895 AN: 5164

South Asian (SAS) AF: 0.625 AC: 3010 AN: 4814

European-Finnish (FIN) AF: 0.656 AC: 6903 AN: 10520

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.704 AC: 47809 AN: 67896

Other (OTH) AF: 0.605 AC: 1272 AN: 2104

Alfa AF: 0.620 Hom.: 5857

Bravo AF: 0.517

Asia WGS AF: 0.565 AC: 1960 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 20, 2018

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurofibromatosis, familial spinal Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2905876; hg19: chr17-29541437;