19-7170704-C-G

Variant names:

• chr19-7170704-C-G
• rs121913158
• NM_000208.4:c.1316G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000208.4(INSR):​c.1316G>C​(p.Trp439Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56
• Publications: 5 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-7170704-C-G is Pathogenic according to our data. Variant chr19-7170704-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14710.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 21		NP_001073285.1
INSR	XM_011527988.3	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 22		XP_011526290.2
INSR	XM_011527989.4	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1316G>C	p.Trp439Ser	missense_variant	Exon 6 of 21	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1291G>C		non_coding_transcript_exon_variant	Exon 6 of 10	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leprechaunism syndrome Pathogenic:1

May 13, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.5	M;M
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.93		Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);
MVP		0.96
MPC		2.3
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121913158; hg19: chr19-7170715;