rs143523271

Positions:

• chr19-7150521-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The ENST00000302850.10(INSR):​c.2243C>T​(p.Ser748Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,056 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: INSR ENST00000302850.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 2.80

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 Benign. Variant got -8 ACMG points.

• 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.
• BP6: Variant 19-7150521-G-A is Benign according to our data. Variant chr19-7150521-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211190.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4}. Variant chr19-7150521-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00111 (169/152250) while in subpopulation NFE AF= 0.00209 (142/68052). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.2243C>T	p.Ser748Leu	missense_variant	11/22	ENST00000302850.10	NP_000199.2
INSR	XM_011527988.3	c.2243C>T	p.Ser748Leu	missense_variant	11/22		XP_011526290.2
INSR	NM_001079817.3	c.2231+2205C>T		intron_variant			NP_001073285.1
INSR	XM_011527989.4	c.2231+2205C>T		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2243C>T	p.Ser748Leu	missense_variant	11/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.2231+2205C>T		intron_variant		1		ENSP00000342838	P3

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000796 AC: 200 AN: 251258 Hom.: 0 AF XY: 0.000751 AC XY: 102 AN XY: 135810

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00190 AC: 2784 AN: 1461806 Hom.: 8 Cov.: 31 AF XY: 0.00181 AC XY: 1319 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74384

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.00147

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	Reported previously in the heterozygous state with a second INSR variant in a female with type A insulin resistance in childhood who had normal weight and body mass indices (Wei et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28093873, 22939401) -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 12, 2015

- -

Rabson-Mendenhall syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Leprechaunism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 24, 2017

ACMG Criteria:BS2 (6 controls in T2DM), PP3 (2 predictors), BP4 (6 predictors) -

INSR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.13
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.34
MVP		0.86
MPC		0.69
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: 11

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

Publications

LitVar

Other links and lift over

dbSNP: rs143523271; hg19: chr19-7150532;