chr19-7122733-A-G

Position:

• chr19-7122733-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PP2 PP3_Moderate BS1_Supporting

The NM_000208.4(INSR):​c.3410T>C​(p.Ile1137Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.81

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 4 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity INSR_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_000208.4
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000342 (5/1461882) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.3410T>C	p.Ile1137Thr	missense_variant	19/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.3374T>C	p.Ile1125Thr	missense_variant	18/21		NP_001073285.1
INSR	XM_011527988.3	c.3407T>C	p.Ile1136Thr	missense_variant	19/22		XP_011526290.2
INSR	XM_011527989.4	c.3371T>C	p.Ile1124Thr	missense_variant	18/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.3410T>C	p.Ile1137Thr	missense_variant	19/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.3374T>C	p.Ile1125Thr	missense_variant	18/21	1		ENSP00000342838	P3
INSR	ENST00000593970.1	n.256T>C		non_coding_transcript_exon_variant	3/3	2
INSR	ENST00000601099.1	n.321T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251476 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2021	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 435516). This variant has not been reported in the literature in individuals affected with INSR-related conditions. This variant is present in population databases (rs775854644, ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 1137 of the INSR protein (p.Ile1137Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 27, 2017

- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.59	.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.31	B;B
Vest4		0.92
MutPred		0.76		.;Gain of disorder (P = 0.0167);
MVP		0.93
MPC		1.8
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775854644; hg19: chr19-7122744;