rs1800601

Variant names:

• chr1-156815825-G-A
• rs1800601
• NM_003975.4:c.123+181C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-156815825-G-A
• chr1-156815825-G-C
• chr1-156815825-G-T

Variant summary

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

The NM_001007792.1(NTRK1):​c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,396 control chromosomes in the GnomAD database, including 370,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31223 hom., cov: 31)
  • Exomes 𝑓: 0.68 (338909 hom.)
• Consequence: NTRK1 NM_001007792.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.84
• Publications: 30 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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=-0.92).
• BP6: Variant 1-156815825-G-A is Benign according to our data. Variant chr1-156815825-G-A is described in ClinVar as Benign. ClinVar VariationId is 380853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007792.1. 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.123+181C>T		intron	N/A	NP_003966.2	Q9NP31-1
	NTRK1	NM_001007792.1		c.-5G>A		5_prime_UTR	Exon 1 of 17	NP_001007793.1	P04629-3
	SH2D2A	NM_001161441.2		c.123+181C>T		intron	N/A	NP_001154913.1	Q9NP31-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D2A	ENST00000368199.8	TSL:1 MANE Select	c.123+181C>T		intron	N/A	ENSP00000357182.3	Q9NP31-1
	SH2D2A	ENST00000392306.2	TSL:1	c.123+181C>T		intron	N/A	ENSP00000376123.2	Q9NP31-2
	SH2D2A	ENST00000368198.8	TSL:1	c.69+181C>T		intron	N/A	ENSP00000357181.3	Q9NP31-4

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96440 AN: 151824 Hom.: 31197 Cov.: 31

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.674 AC: 169366 AN: 251274 AF XY: 0.676

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.698

Gnomad EAS exome AF: 0.818

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.679 AC: 992629 AN: 1461454 Hom.: 338909 Cov.: 57 AF XY: 0.679 AC XY: 493795 AN XY: 727032

African (AFR) AF: 0.491 AC: 16422 AN: 33470

American (AMR) AF: 0.693 AC: 31008 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 18018 AN: 26134

East Asian (EAS) AF: 0.817 AC: 32421 AN: 39698

South Asian (SAS) AF: 0.657 AC: 56669 AN: 86236

European-Finnish (FIN) AF: 0.650 AC: 34732 AN: 53414

Middle Eastern (MID) AF: 0.719 AC: 4148 AN: 5766

European-Non Finnish (NFE) AF: 0.682 AC: 758001 AN: 1111638

Other (OTH) AF: 0.682 AC: 41210 AN: 60382

GnomAD4 genome AF: 0.635 AC: 96511 AN: 151942 Hom.: 31223 Cov.: 31 AF XY: 0.640 AC XY: 47513 AN XY: 74258

African (AFR) AF: 0.506 AC: 20947 AN: 41422

American (AMR) AF: 0.696 AC: 10621 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2369 AN: 3468

East Asian (EAS) AF: 0.819 AC: 4213 AN: 5146

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

European-Finnish (FIN) AF: 0.661 AC: 6988 AN: 10566

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 45960 AN: 67934

Other (OTH) AF: 0.643 AC: 1357 AN: 2110

Alfa AF: 0.665 Hom.: 143032

Bravo AF: 0.635

Asia WGS AF: 0.702 AC: 2441 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.682

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary insensitivity to pain with anhidrosis (1)
-	-	1	not provided (1)
-	-	1	X-linked lymphoproliferative disease due to SH2D1A deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.50
DANN	Benign	0.78
PhyloP100		-1.8
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800601; hg19: chr1-156785617; COSMIC: COSV63884607; COSMIC: COSV63884607;