19-7184227-G-T

Variant names:

• chr19-7184227-G-T
• rs6510959
• NM_000208.4:c.974+89C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000208.4(INSR):​c.974+89C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000976 in 1,024,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.756
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.974+89C>A		intron_variant	Intron 3 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.974+89C>A		intron_variant	Intron 3 of 20		NP_001073285.1
INSR	XM_011527988.3	c.974+89C>A		intron_variant	Intron 3 of 21		XP_011526290.2
INSR	XM_011527989.4	c.974+89C>A		intron_variant	Intron 3 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.974+89C>A		intron_variant	Intron 3 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.974+89C>A		intron_variant	Intron 3 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.949+89C>A		intron_variant	Intron 3 of 9	1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 9.76e-7 AC: 1 AN: 1024392 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 521570

⚠️ 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: 24966

American (AMR) AF: 0.00 AC: 0 AN: 37852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22856

East Asian (EAS) AF: 0.00 AC: 0 AN: 36398

South Asian (SAS) AF: 0.00 AC: 0 AN: 73546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3398

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 736136

Other (OTH) AF: 0.00 AC: 0 AN: 45826

⚠️ 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.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.050
DANN	Benign	0.85
PhyloP100		-0.76

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: rs6510959; hg19: chr19-7184238;