19-7112336-C-CA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000208.4(INSR):c.*4719_*4720insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 150,162 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.598

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0016 (241/150162) while in subpopulation EAS AF= 0.0111 (57/5132). AF 95% confidence interval is 0.0088. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.*4719_*4720insT		3_prime_UTR_variant	22/22	ENST00000302850.10
INSR	NM_001079817.3	c.*4719_*4720insT		3_prime_UTR_variant	21/21
INSR	XM_011527988.3	c.*4719_*4720insT		3_prime_UTR_variant	22/22
INSR	XM_011527989.4	c.*4719_*4720insT		3_prime_UTR_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.*4719_*4720insT		3_prime_UTR_variant	22/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.*4719_*4720insT		3_prime_UTR_variant	21/21	1		P3

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 241 AN: 150048 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000931

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000487

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.00160 AC: 241 AN: 150162 Hom.: 2 Cov.: 32 AF XY: 0.00176 AC XY: 129 AN XY: 73260

Gnomad4 AFR AF: 0.000366

Gnomad4 AMR AF: 0.000930

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0111

Gnomad4 SAS AF: 0.00148

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000482

Bravo AF: 0.00121

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Rabson-Mendenhall syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leprechaunism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs543556010; hg19: chr19-7112347;