rs79020702

Variant names:

• chr1-156842014-C-G
• rs79020702
• NM_014215.3:c.3397+98G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014215.3(INSRR):​c.3397+98G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,585,664 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: INSRR NM_014215.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.178
• Publications: 0 publications found

Genes affected

INSRR (HGNC:6093): (insulin receptor related receptor) Enables transmembrane receptor protein tyrosine kinase activity. Involved in actin cytoskeleton reorganization; cellular response to alkaline pH; and protein autophosphorylation. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-156842014-C-G is Benign according to our data. Variant chr1-156842014-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1215621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0047 (715/152272) while in subpopulation AFR AF = 0.0164 (682/41562). AF 95% confidence interval is 0.0154. There are 6 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014215.3. 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
	INSRR	NM_014215.3	MANE Select	c.3397+98G>C		intron	N/A	NP_055030.1	P14616
	NTRK1	NM_001007792.1		c.10-67C>G		intron	N/A	NP_001007793.1	P04629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSRR	ENST00000368195.4	TSL:1 MANE Select	c.3397+98G>C		intron	N/A	ENSP00000357178.3	P14616
	NTRK1	ENST00000392302.7	TSL:5	c.-63-67C>G		intron	N/A	ENSP00000376120.3	A0A6Q8PHG5
	NTRK1	ENST00000674537.2		c.-63-67C>G		intron	N/A	ENSP00000502725.1	A0A6Q8PHG5

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152154 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000488 AC: 700 AN: 1433392 Hom.: 4 Cov.: 31 AF XY: 0.000405 AC XY: 288 AN XY: 711404

African (AFR) AF: 0.0188 AC: 617 AN: 32892

American (AMR) AF: 0.000616 AC: 25 AN: 40564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52116

Middle Eastern (MID) AF: 0.000760 AC: 4 AN: 5264

European-Non Finnish (NFE) AF: 0.00000639 AC: 7 AN: 1095896

Other (OTH) AF: 0.000758 AC: 45 AN: 59354

GnomAD4 genome AF: 0.00470 AC: 715 AN: 152272 Hom.: 6 Cov.: 31 AF XY: 0.00439 AC XY: 327 AN XY: 74460

African (AFR) AF: 0.0164 AC: 682 AN: 41562

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00520 Hom.: 0

Bravo AF: 0.00587

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.63
PhyloP100		-0.18
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: rs79020702; hg19: chr1-156811806;