19-7167940-T-G

Position:

• chr19-7167940-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.1610+28A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,784 control chromosomes in the GnomAD database, including 49,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4518 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45477 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0650

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-7167940-T-G is Benign according to our data. Variant chr19-7167940-T-G is described in ClinVar as [Benign]. Clinvar id is 439831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1610+28A>C		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1610+28A>C		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.1610+28A>C		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.1610+28A>C		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1610+28A>C		intron_variant		1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1610+28A>C		intron_variant		1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1585+28A>C		intron_variant		1
INSR	ENST00000600492.1	c.11+28A>C		intron_variant		5		ENSP00000473170.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36686 AN: 151696 Hom.: 4508 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.259 AC: 64942 AN: 251092 Hom.: 8356 AF XY: 0.260 AC XY: 35306 AN XY: 135762

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.244

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.247 AC: 361367 AN: 1460970 Hom.: 45477 Cov.: 34 AF XY: 0.248 AC XY: 180316 AN XY: 726788

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.253

GnomAD4 genome AF: 0.242 AC: 36730 AN: 151814 Hom.: 4518 Cov.: 31 AF XY: 0.246 AC XY: 18269 AN XY: 74132

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.277

Alfa AF: 0.249 Hom.: 1057

Bravo AF: 0.233

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.25
DANN	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2860177; hg19: chr19-7167951; COSMIC: COSV57156805;