rs1135401738

Variant names:

• chr19-7142833-G-A
• rs1135401738
• NM_000208.4:c.2525C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000208.4(INSR):​c.2525C>T​(p.Ala842Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as no classification for the single variant (no stars). Synonymous variant affecting the same amino acid position (i.e. A842A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2525C>T	p.Ala842Val	missense_variant	Exon 12 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2489C>T	p.Ala830Val	missense_variant	Exon 11 of 21		NP_001073285.1
INSR	XM_011527988.3	c.2525C>T	p.Ala842Val	missense_variant	Exon 12 of 22		XP_011526290.2
INSR	XM_011527989.4	c.2489C>T	p.Ala830Val	missense_variant	Exon 11 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2525C>T	p.Ala842Val	missense_variant	Exon 12 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2489C>T	p.Ala830Val	missense_variant	Exon 11 of 21	1		ENSP00000342838.4
INSR	ENST00000597211.1	n.208C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249780 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	-0.0013	T
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.49
Sift	Benign	0.093	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.79	P;P
Vest4		0.68
MutPred		0.33		.;Loss of disorder (P = 0.09);
MVP		0.92
MPC		1.7
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1135401738; hg19: chr19-7142844;