19-7268427-G-A

Variant names:

• chr19-7268427-G-A
• rs7248939
• NM_000208.4:c.101-531C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.101-531C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 984,182 control chromosomes in the GnomAD database, including 61,881 homozygotes. 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: 𝑓 0.37 (10586 hom., cov: 30)
  • Exomes 𝑓: 0.35 (51295 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 7 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

ENSG00000306258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.101-531C>T		intron_variant	Intron 1 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.101-531C>T		intron_variant	Intron 1 of 20		NP_001073285.1
INSR	XM_011527988.3	c.101-531C>T		intron_variant	Intron 1 of 21		XP_011526290.2
INSR	XM_011527989.4	c.101-531C>T		intron_variant	Intron 1 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.101-531C>T		intron_variant	Intron 1 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.101-531C>T		intron_variant	Intron 1 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.76-531C>T		intron_variant	Intron 1 of 9	1
ENSG00000306258	ENST00000816520.1	n.1059G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55921 AN: 151616 Hom.: 10563 Cov.: 30

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.349 AC: 290608 AN: 832448 Hom.: 51295 Cov.: 29 AF XY: 0.348 AC XY: 133756 AN XY: 384424

African (AFR) AF: 0.393 AC: 6189 AN: 15768

American (AMR) AF: 0.387 AC: 381 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 1413 AN: 5150

East Asian (EAS) AF: 0.605 AC: 2192 AN: 3624

South Asian (SAS) AF: 0.359 AC: 5907 AN: 16452

European-Finnish (FIN) AF: 0.351 AC: 97 AN: 276

Middle Eastern (MID) AF: 0.348 AC: 563 AN: 1620

European-Non Finnish (NFE) AF: 0.347 AC: 264119 AN: 761288

Other (OTH) AF: 0.357 AC: 9747 AN: 27286

GnomAD4 genome AF: 0.369 AC: 55978 AN: 151734 Hom.: 10586 Cov.: 30 AF XY: 0.370 AC XY: 27406 AN XY: 74130

African (AFR) AF: 0.392 AC: 16218 AN: 41332

American (AMR) AF: 0.361 AC: 5502 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3468

East Asian (EAS) AF: 0.605 AC: 3114 AN: 5144

South Asian (SAS) AF: 0.352 AC: 1697 AN: 4816

European-Finnish (FIN) AF: 0.344 AC: 3619 AN: 10520

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.346 AC: 23506 AN: 67918

Other (OTH) AF: 0.367 AC: 770 AN: 2100

Alfa AF: 0.353 Hom.: 7896

Bravo AF: 0.371

Asia WGS AF: 0.503 AC: 1749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.074
DANN	Benign	0.47
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs7248939; hg19: chr19-7268438;