rs199641099

Variant names:

• chr17-31356628-G-A
• rs199641099
• NM_001042492.3:c.7738+46G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31356628-G-A
• chr17-31356628-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.7738+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,609,164 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (81 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0580
• Publications: 1 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=-0.79).
• BP6: Variant 17-31356628-G-A is Benign according to our data. Variant chr17-31356628-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00457 (695/152170) while in subpopulation SAS AF = 0.0149 (72/4828). AF 95% confidence interval is 0.0121. There are 2 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 695 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.7738+46G>A		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.7675+46G>A		intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.7738+46G>A		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.7675+46G>A		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*2903+46G>A		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00661 AC: 1639 AN: 247902 AF XY: 0.00772

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00635

Gnomad NFE exome AF: 0.00664

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00746 AC: 10870 AN: 1456994 Hom.: 81 Cov.: 30 AF XY: 0.00801 AC XY: 5809 AN XY: 724798

African (AFR) AF: 0.000839 AC: 28 AN: 33380

American (AMR) AF: 0.00205 AC: 91 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 84 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.0195 AC: 1671 AN: 85846

European-Finnish (FIN) AF: 0.00688 AC: 366 AN: 53222

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5734

European-Non Finnish (NFE) AF: 0.00739 AC: 8188 AN: 1108626

Other (OTH) AF: 0.00627 AC: 377 AN: 60134

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74432

African (AFR) AF: 0.00142 AC: 59 AN: 41542

American (AMR) AF: 0.00163 AC: 25 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4828

European-Finnish (FIN) AF: 0.00632 AC: 67 AN: 10608

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.00645 AC: 438 AN: 67926

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00524 Hom.: 1

Bravo AF: 0.00400

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 15, 2018

GeneDx

Significance: Likely 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.

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1-related disorder Benign:1

May 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.61
PhyloP100		0.058
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199641099; hg19: chr17-29683646; COSMIC: COSV104420563;