1-156815821-A-G

Variant names:

• chr1-156815821-A-G
• rs200646544
• NM_003975.4:c.123+185T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003975.4(SH2D2A):​c.123+185T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,848 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: SH2D2A NM_003975.4 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.26
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-156815821-A-G is Benign according to our data. Variant chr1-156815821-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3051205.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.123+185T>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+185T>C		intron_variant	Intron 2 of 8	1	NM_003975.4	ENSP00000357182.3

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 151980 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000855 AC: 215 AN: 251474 AF XY: 0.000773

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00129 AC: 1885 AN: 1461868 Hom.: 1 Cov.: 30 AF XY: 0.00129 AC XY: 935 AN XY: 727240

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 117 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00147 AC: 1638 AN: 1111986

Other (OTH) AF: 0.00119 AC: 72 AN: 60396

GnomAD4 genome AF: 0.00121 AC: 184 AN: 151980 Hom.: 1 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74234

African (AFR) AF: 0.000218 AC: 9 AN: 41376

American (AMR) AF: 0.000917 AC: 14 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 67972

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00137

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NTRK1-related disorder Benign:1

May 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.56
PhyloP100		-2.3
PromoterAI		0.040	Neutral
Mutation Taster		=300/0	polymorphism

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: rs200646544; hg19: chr1-156785613; COSMIC: COSV104679413;