1-156815970-AG-A

Variant names:

• chr1-156815970-AG-A
• rs11325907
• NM_003975.4:c.123+35delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003975.4(SH2D2A):​c.123+35delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (25694 hom., cov: 0)
  • Exomes 𝑓: 0.64 (304802 hom.)
• Consequence: SH2D2A NM_003975.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.239
• Publications: 5 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 -10 ACMG points.

• BP6: Variant 1-156815970-AG-A is Benign according to our data. Variant chr1-156815970-AG-A is described in ClinVar as [Benign]. Clinvar id is 1225268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.123+35delC		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+35delC		intron_variant	Intron 2 of 8	1	NM_003975.4	ENSP00000357182.3

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85422 AN: 151364 Hom.: 25680 Cov.: 0

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.584

GnomAD2 exomes AF: 0.631 AC: 154698 AN: 245012 AF XY: 0.636

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.629

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.644 AC: 936630 AN: 1455468 Hom.: 304802 Cov.: 0 AF XY: 0.645 AC XY: 466899 AN XY: 724024

African (AFR) AF: 0.314 AC: 10469 AN: 33372

American (AMR) AF: 0.663 AC: 29393 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 15346 AN: 26016

East Asian (EAS) AF: 0.817 AC: 32346 AN: 39604

South Asian (SAS) AF: 0.652 AC: 55904 AN: 85752

European-Finnish (FIN) AF: 0.632 AC: 33669 AN: 53252

Middle Eastern (MID) AF: 0.638 AC: 3674 AN: 5760

European-Non Finnish (NFE) AF: 0.648 AC: 717594 AN: 1107236

Other (OTH) AF: 0.635 AC: 38235 AN: 60176

GnomAD4 genome AF: 0.564 AC: 85472 AN: 151486 Hom.: 25694 Cov.: 0 AF XY: 0.570 AC XY: 42132 AN XY: 73966

African (AFR) AF: 0.337 AC: 13925 AN: 41354

American (AMR) AF: 0.646 AC: 9843 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2011 AN: 3454

East Asian (EAS) AF: 0.818 AC: 4172 AN: 5102

South Asian (SAS) AF: 0.647 AC: 3120 AN: 4822

European-Finnish (FIN) AF: 0.647 AC: 6805 AN: 10518

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43496 AN: 67718

Other (OTH) AF: 0.582 AC: 1225 AN: 2104

Alfa AF: 0.537 Hom.: 3005

Bravo AF: 0.558

Asia WGS AF: 0.684 AC: 2379 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=97/3	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: rs11325907; hg19: chr1-156785762;