rs745857330

chr19-7293851-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2 PP3 BS1_Supporting

The NM_000208.4(INSR):c.41T>C(p.Leu14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,262,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 1.43

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.

• PP2: Missense variant where missense usually causes diseases, INSR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000529 (80/151110) while in subpopulation AMR AF= 0.00151 (23/15196). AF 95% confidence interval is 0.00103. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. 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	UniProt
INSR	NM_000208.4	c.41T>C	p.Leu14Pro	missense_variant	1/22	ENST00000302850.10
INSR	NM_001079817.3	c.41T>C	p.Leu14Pro	missense_variant	1/21
INSR	XM_011527988.3	c.41T>C	p.Leu14Pro	missense_variant	1/22
INSR	XM_011527989.4	c.41T>C	p.Leu14Pro	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.41T>C	p.Leu14Pro	missense_variant	1/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.41T>C	p.Leu14Pro	missense_variant	1/21	1		P3
INSR	ENST00000598216.1	n.16T>C		non_coding_transcript_exon_variant	1/10	1

Frequencies

GnomAD3 genomes AF: 0.000530 AC: 80 AN: 151004 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000666

Gnomad OTH AF: 0.000968

GnomAD3 exomes AF: 0.000240 AC: 3 AN: 12484 Hom.: 0 AF XY: 0.000241 AC XY: 2 AN XY: 8290

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: 0.000300

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000388 AC: 431 AN: 1111716 Hom.: 1 Cov.: 29 AF XY: 0.000393 AC XY: 211 AN XY: 536368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000454

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000529 AC: 80 AN: 151110 Hom.: 0 Cov.: 33 AF XY: 0.000528 AC XY: 39 AN XY: 73858

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000666

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000648 Hom.: 0

Bravo AF: 0.000635

ExAC AF: 0.000136 AC: 2

Asia WGS AF: 0.000295 AC: 1 AN: 3408

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2017	The L14P variant in the INSR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L14P variant is not observed at a significant frequency in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L14P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret L14P as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.41T>C (p.L14P) alteration is located in exon 1 (coding exon 1) of the INSR gene. This alteration results from a T to C substitution at nucleotide position 41, causing the leucine (L) at amino acid position 14 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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. -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Apr 09, 2018

ACMG criteria: PP3 (4 predictors), BP4 (5 predictors), called VUS in ClinVar by Illumina, Emory and GeneDx, (PM1) residue 14 is within the signal peptide (PMIDs: 8257688, 2983222, 2211730), REVEL 0.52=VUS -

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. -

Hyperinsulinism due to INSR deficiency Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in INSR gene can lead to insulin resistance, which presents as impaired glucose tolerance, early onset type 2 diabetes, post prandial hyperglycemia and increased insulin requirement in type 1 diabetes. These mutations in INSR gene can also predispose to coronary artery disease, metabolic syndrome, polycystic ovarian disease and non alcoholic fatty liver disease.However, the role of this particular variant rs745857330 with early onset diabetes mellitus is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Benign	0.89
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.40	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.85	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.089	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;D
Vest4		0.62
MutPred		0.70		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.93
MPC		1.2
ClinPred		0.11	T
GERP RS		3.0
Varity_R		0.47
gMVP		0.63

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: rs745857330; hg19: chr19-7293862;