rs3815156

Variant names:

• chr17-31358132-A-G
• rs3815156
• NM_001042492.3:c.7971-348A>G

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.7971-348A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 353,120 control chromosomes in the GnomAD database, including 8,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3049 hom., cov: 32)
  • Exomes 𝑓: 0.21 (5376 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.82
• Publications: 9 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=-0.83).
• BP6: Variant 17-31358132-A-G is Benign according to our data. Variant chr17-31358132-A-G is described in ClinVar as Benign. ClinVar VariationId is 561764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7971-348A>G		intron_variant	Intron 54 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.7908-348A>G		intron_variant	Intron 53 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7971-348A>G		intron_variant	Intron 54 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26579 AN: 152028 Hom.: 3040 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.213 AC: 42899 AN: 200972 Hom.: 5376 Cov.: 0 AF XY: 0.222 AC XY: 24201 AN XY: 109098

African (AFR) AF: 0.0541 AC: 316 AN: 5844

American (AMR) AF: 0.321 AC: 2400 AN: 7488

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 772 AN: 5404

East Asian (EAS) AF: 0.437 AC: 4008 AN: 9164

South Asian (SAS) AF: 0.288 AC: 9724 AN: 33806

European-Finnish (FIN) AF: 0.236 AC: 2150 AN: 9126

Middle Eastern (MID) AF: 0.146 AC: 112 AN: 766

European-Non Finnish (NFE) AF: 0.179 AC: 21298 AN: 118942

Other (OTH) AF: 0.203 AC: 2119 AN: 10432

GnomAD4 genome AF: 0.175 AC: 26607 AN: 152148 Hom.: 3049 Cov.: 32 AF XY: 0.184 AC XY: 13651 AN XY: 74366

African (AFR) AF: 0.0583 AC: 2422 AN: 41552

American (AMR) AF: 0.296 AC: 4522 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2296 AN: 5172

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4818

European-Finnish (FIN) AF: 0.240 AC: 2538 AN: 10562

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12240 AN: 67980

Other (OTH) AF: 0.167 AC: 354 AN: 2116

Alfa AF: 0.167 Hom.: 359

Bravo AF: 0.172

Asia WGS AF: 0.359 AC: 1244 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.41
PhyloP100		2.8
PromoterAI		0.00060	Neutral
Mutation Taster		=96/4	polymorphism (auto)

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: rs3815156; hg19: chr17-29685150;