rs121913147

Positions:

• chr19-7170554-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2 PP3_Moderate PP5

The NM_000208.4(INSR):​c.1466A>G​(p.Asn489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 19-7170554-T-C is Pathogenic according to our data. Variant chr19-7170554-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14695.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1466A>G	p.Asn489Ser	missense_variant	6/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1466A>G	p.Asn489Ser	missense_variant	6/21		NP_001073285.1
INSR	XM_011527988.3	c.1466A>G	p.Asn489Ser	missense_variant	6/22		XP_011526290.2
INSR	XM_011527989.4	c.1466A>G	p.Asn489Ser	missense_variant	6/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1466A>G	p.Asn489Ser	missense_variant	6/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.1466A>G	p.Asn489Ser	missense_variant	6/21	1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.1441A>G		non_coding_transcript_exon_variant	6/10	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460634 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1990

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 2365819, 27896077) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.77		Gain of glycosylation at N489 (P = 0.0271);Gain of glycosylation at N489 (P = 0.0271);
MVP		0.98
MPC		1.1
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.99

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: rs121913147; hg19: chr19-7170565;