rs121913153

chr19-7267659-C-Achr19-7267659-C-Gchr19-7267659-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000208.4(INSR):c.338G>T(p.Arg113Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-7267659-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 14703.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, INSR

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.338G>T	p.Arg113Leu	missense_variant	2/22	ENST00000302850.10
INSR	NM_001079817.3	c.338G>T	p.Arg113Leu	missense_variant	2/21
INSR	XM_011527988.3	c.338G>T	p.Arg113Leu	missense_variant	2/22
INSR	XM_011527989.4	c.338G>T	p.Arg113Leu	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.338G>T	p.Arg113Leu	missense_variant	2/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.338G>T	p.Arg113Leu	missense_variant	2/21	1		P3
INSR	ENST00000598216.1	n.313G>T		non_coding_transcript_exon_variant	2/10	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.75	N;N
MutationTaster	Benign	0.78	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.11	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.060	B;B
Vest4		0.58
MutPred		0.73		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.91
MPC		1.3
ClinPred		0.47	T
GERP RS		5.2
Varity_R		0.37
gMVP		0.70

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: rs121913153; hg19: chr19-7267670;