19-7184507-G-T

Position:

• chr19-7184507-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000208.4(INSR):​c.783C>A​(p.Asp261Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. D261D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12159434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.783C>A	p.Asp261Glu	missense_variant	3/22	ENST00000302850.10
INSR	NM_001079817.3	c.783C>A	p.Asp261Glu	missense_variant	3/21
INSR	XM_011527988.3	c.783C>A	p.Asp261Glu	missense_variant	3/22
INSR	XM_011527989.4	c.783C>A	p.Asp261Glu	missense_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.783C>A	p.Asp261Glu	missense_variant	3/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.783C>A	p.Asp261Glu	missense_variant	3/21	1		P3
INSR	ENST00000598216.1	n.758C>A		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.62
DANN	Benign	0.85
DEOGEN2	Uncertain	0.49	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	-0.045	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.28
Sift	Benign	0.69	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.54		Gain of methylation at R263 (P = 0.3384);Gain of methylation at R263 (P = 0.3384);
MVP		0.68
MPC		0.70
ClinPred		0.045	T
GERP RS		-8.6
Varity_R		0.18
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs891087; hg19: chr19-7184518;