1-156815979-A-G

Variant names:

• chr1-156815979-A-G
• rs7546838
• NM_003975.4:c.123+27T>C

Variant summary

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

The NM_003975.4(SH2D2A):​c.123+27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,608,350 control chromosomes in the GnomAD database, including 335,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27797 hom., cov: 32)
  • Exomes 𝑓: 0.65 (307322 hom.)
• Consequence: SH2D2A NM_003975.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.31
• Publications: 9 publications found

Genes affected

SH2D2A (HGNC:10821): (SH2 domain containing 2A) This gene encodes an adaptor protein thought to function in T-cell signal transduction. A related protein in mouse is responsible for the activation of lymphocyte-specific protein-tyrosine kinase and functions in downstream signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

NTRK1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-156815979-A-G is Benign according to our data. Variant chr1-156815979-A-G is described in ClinVar as [Benign]. Clinvar id is 667767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.123+27T>C		intron_variant	Intron 2 of 8	ENST00000368199.8	NP_003966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D2A	ENST00000368199.8	c.123+27T>C		intron_variant	Intron 2 of 8	1	NM_003975.4	ENSP00000357182.3

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90538 AN: 151320 Hom.: 27774 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.638

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.606

GnomAD2 exomes AF: 0.641 AC: 157680 AN: 246056 AF XY: 0.643

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.647 AC: 943044 AN: 1456910 Hom.: 307322 Cov.: 39 AF XY: 0.648 AC XY: 469662 AN XY: 724586

African (AFR) AF: 0.434 AC: 14498 AN: 33394

American (AMR) AF: 0.671 AC: 29736 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 15371 AN: 26038

East Asian (EAS) AF: 0.817 AC: 32367 AN: 39628

South Asian (SAS) AF: 0.652 AC: 56017 AN: 85864

European-Finnish (FIN) AF: 0.633 AC: 33689 AN: 53260

Middle Eastern (MID) AF: 0.646 AC: 3724 AN: 5764

European-Non Finnish (NFE) AF: 0.648 AC: 718786 AN: 1108450

Other (OTH) AF: 0.645 AC: 38856 AN: 60220

GnomAD4 genome AF: 0.598 AC: 90607 AN: 151440 Hom.: 27797 Cov.: 32 AF XY: 0.603 AC XY: 44603 AN XY: 73952

African (AFR) AF: 0.455 AC: 18810 AN: 41296

American (AMR) AF: 0.659 AC: 10039 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2015 AN: 3456

East Asian (EAS) AF: 0.817 AC: 4175 AN: 5110

South Asian (SAS) AF: 0.648 AC: 3123 AN: 4822

European-Finnish (FIN) AF: 0.646 AC: 6796 AN: 10520

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.642 AC: 43497 AN: 67706

Other (OTH) AF: 0.605 AC: 1275 AN: 2108

Alfa AF: 0.595 Hom.: 5292

Bravo AF: 0.597

Asia WGS AF: 0.694 AC: 2413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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. -

Hereditary insensitivity to pain with anhidrosis Benign:1

Jul 08, 2021

Genome-Nilou Lab

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	-0.86
CADD	Benign	0.31
DANN	Benign	0.28
PhyloP100		-1.3
PromoterAI		0.038	Neutral
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: rs7546838; hg19: chr1-156785771; COSMIC: COSV63884348; COSMIC: COSV63884348;