19-7112870-A-G

Position:

• chr19-7112870-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000208.4(INSR):​c.*4186T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 152,086 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.058 (732 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.0300

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7112870-A-G is Benign according to our data. Variant chr19-7112870-A-G is described in ClinVar as [Benign]. Clinvar id is 330356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.*4186T>C		3_prime_UTR_variant	22/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.*4186T>C		3_prime_UTR_variant	21/21		NP_001073285.1
INSR	XM_011527988.3	c.*4186T>C		3_prime_UTR_variant	22/22		XP_011526290.2
INSR	XM_011527989.4	c.*4186T>C		3_prime_UTR_variant	21/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.*4186T>C		3_prime_UTR_variant	22/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.*4186T>C		3_prime_UTR_variant	21/21	1		ENSP00000342838	P3

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8833 AN: 151968 Hom.: 727 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.0493

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

GnomAD4 genome AF: 0.0582 AC: 8856 AN: 152086 Hom.: 732 Cov.: 31 AF XY: 0.0585 AC XY: 4348 AN XY: 74364

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0287

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0235 Hom.: 59

Bravo AF: 0.0665

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1366600; hg19: chr19-7112881;