NM_003975.4:c.111G>C

Variant names:

• chr1-156816018-C-G
• rs145574758
• NM_003975.4:c.111G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003975.4(SH2D2A):​c.111G>C​(p.Leu37Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,613,916 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (35 hom.)
• Consequence: SH2D2A NM_003975.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72
• Publications: 2 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-156816018-C-G is Benign according to our data. Variant chr1-156816018-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1176211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003975.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D2A	NM_003975.4	MANE Select	c.111G>C	p.Leu37Leu	synonymous	Exon 2 of 9	NP_003966.2	Q9NP31-1
	SH2D2A	NM_001161441.2		c.111G>C	p.Leu37Leu	synonymous	Exon 2 of 9	NP_001154913.1	Q9NP31-2
	SH2D2A	NM_001161444.2		c.111G>C	p.Leu37Leu	synonymous	Exon 2 of 8	NP_001154916.1	Q9NP31-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D2A	ENST00000368199.8	TSL:1 MANE Select	c.111G>C	p.Leu37Leu	synonymous	Exon 2 of 9	ENSP00000357182.3	Q9NP31-1
	SH2D2A	ENST00000392306.2	TSL:1	c.111G>C	p.Leu37Leu	synonymous	Exon 2 of 9	ENSP00000376123.2	Q9NP31-2
	SH2D2A	ENST00000368198.8	TSL:1	c.57G>C	p.Leu19Leu	synonymous	Exon 2 of 9	ENSP00000357181.3	Q9NP31-4

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00504 AC: 1264 AN: 250772 AF XY: 0.00520

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00577 AC: 8432 AN: 1461644 Hom.: 35 Cov.: 34 AF XY: 0.00578 AC XY: 4202 AN XY: 727112

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00367 AC: 164 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00409 AC: 353 AN: 86212

European-Finnish (FIN) AF: 0.00258 AC: 138 AN: 53398

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.00656 AC: 7293 AN: 1111898

Other (OTH) AF: 0.00512 AC: 309 AN: 60384

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74452

African (AFR) AF: 0.00111 AC: 46 AN: 41550

American (AMR) AF: 0.00379 AC: 58 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00662 AC: 450 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00621 Hom.: 0

Bravo AF: 0.00408

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00789

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.68
PhyloP100		-1.7
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs145574758; hg19: chr1-156785810;