19-7293887-G-T

Variant names:

• chr19-7293887-G-T
• rs7508518
• NM_000208.4:c.5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000208.4(INSR):​c.5C>A​(p.Ala2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,076,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A2G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

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

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

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• 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 Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23192528).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 22	NP_000199.2
	INSR	NM_001079817.3		c.5C>A	p.Ala2Asp	missense	Exon 1 of 21	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 22	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.5C>A	p.Ala2Asp	missense	Exon 1 of 21	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.-21C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076648 Hom.: 0 Cov.: 34 AF XY: 0.00000194 AC XY: 1 AN XY: 515860

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21530

American (AMR) AF: 0.00 AC: 0 AN: 7150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12582

East Asian (EAS) AF: 0.00 AC: 0 AN: 23108

South Asian (SAS) AF: 0.00 AC: 0 AN: 23634

European-Finnish (FIN) AF: 0.0000483 AC: 1 AN: 20702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2770

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 922960

Other (OTH) AF: 0.0000237 AC: 1 AN: 42212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.18	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.46
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.13
Sift	Uncertain	0.020	D
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.22		Loss of MoRF binding (P = 0.0181)
MVP		0.79
MPC		1.1
ClinPred		0.099	T
GERP RS		2.6
PromoterAI		-0.26	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.086
gMVP		0.75
Mutation Taster		=96/4	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: rs7508518; hg19: chr19-7293898;