rs745857330

Variant names:

• chr19-7293851-A-G
• rs745857330
• NM_000208.4:c.41T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Donohue syndrome, insulin-resistance syndrome type A, Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.41T>C	p.Leu14Pro	missense	Exon 1 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.41T>C	p.Leu14Pro	missense	Exon 1 of 21	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.41T>C	p.Leu14Pro	missense	Exon 1 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.41T>C	p.Leu14Pro	missense	Exon 1 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.16T>C		non_coding_transcript_exon	Exon 1 of 10

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

GnomAD2 exomes AF: 0.000240 AC: 3 AN: 12484 AF XY: 0.000241

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 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

African (AFR) AF: 0.00 AC: 0 AN: 22338

American (AMR) AF: 0.000473 AC: 4 AN: 8456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14580

East Asian (EAS) AF: 0.00 AC: 0 AN: 25032

South Asian (SAS) AF: 0.000454 AC: 13 AN: 28648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22662

Middle Eastern (MID) AF: 0.000339 AC: 1 AN: 2946

European-Non Finnish (NFE) AF: 0.000418 AC: 394 AN: 942862

Other (OTH) AF: 0.000430 AC: 19 AN: 44192

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

African (AFR) AF: 0.0000967 AC: 4 AN: 41358

American (AMR) AF: 0.00151 AC: 23 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10286

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000666 AC: 45 AN: 67600

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Hyperinsulinism due to INSR deficiency (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	1	-	Leprechaunism syndrome (1)
-	1	-	Monogenic diabetes (1)
-	1	-	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.52
Sift	Benign	0.089	T
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.62
MutPred		0.70		Gain of loop (P = 3e-04)
MVP		0.93
MPC		1.2
ClinPred		0.11	T
GERP RS		3.0
PromoterAI		-0.018	Neutral
Varity_R		0.47
gMVP		0.63
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs745857330; hg19: chr19-7293862;