rs2953000

Variant names:

• chr17-31182773-C-T
• rs2953000
• NM_001042492.3:c.888+108C>T

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.888+108C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,034,132 control chromosomes in the GnomAD database, including 223,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (26002 hom., cov: 33)
  • Exomes 𝑓: 0.66 (197670 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209
• Publications: 11 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=-0.81).
• BP6: Variant 17-31182773-C-T is Benign according to our data. Variant chr17-31182773-C-T is described in ClinVar as Benign. ClinVar VariationId is 561465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.888+108C>T		intron_variant	Intron 8 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.888+108C>T		intron_variant	Intron 8 of 56		NP_000258.1
NF1	NM_001128147.3	c.888+108C>T		intron_variant	Intron 8 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.888+108C>T		intron_variant	Intron 8 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83639 AN: 151540 Hom.: 26005 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.616

GnomAD4 exome AF: 0.661 AC: 583581 AN: 882474 Hom.: 197670 Cov.: 11 AF XY: 0.663 AC XY: 301109 AN XY: 454342

African (AFR) AF: 0.239 AC: 5234 AN: 21854

American (AMR) AF: 0.517 AC: 17668 AN: 34148

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 16858 AN: 21830

East Asian (EAS) AF: 0.458 AC: 15322 AN: 33490

South Asian (SAS) AF: 0.631 AC: 43250 AN: 68560

European-Finnish (FIN) AF: 0.654 AC: 23521 AN: 35940

Middle Eastern (MID) AF: 0.751 AC: 2395 AN: 3188

European-Non Finnish (NFE) AF: 0.695 AC: 432384 AN: 622326

Other (OTH) AF: 0.655 AC: 26949 AN: 41138

GnomAD4 genome AF: 0.552 AC: 83643 AN: 151658 Hom.: 26002 Cov.: 33 AF XY: 0.547 AC XY: 40573 AN XY: 74106

African (AFR) AF: 0.252 AC: 10422 AN: 41402

American (AMR) AF: 0.557 AC: 8500 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2651 AN: 3464

East Asian (EAS) AF: 0.473 AC: 2439 AN: 5154

South Asian (SAS) AF: 0.616 AC: 2962 AN: 4812

European-Finnish (FIN) AF: 0.653 AC: 6833 AN: 10466

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47658 AN: 67798

Other (OTH) AF: 0.616 AC: 1299 AN: 2108

Alfa AF: 0.585 Hom.: 4310

Bravo AF: 0.533

Asia WGS AF: 0.530 AC: 1842 AN: 3478

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.59
PhyloP100		-0.21
Mutation Taster		=100/0	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: rs2953000; hg19: chr17-29509791; COSMIC: COSV62206118;