19-7170554-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N489D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.67

Publications

7 publications found

Variant links:

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

INSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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, 0.928

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 VariationId is 14695.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.1466A>G	p.Asn489Ser	missense_variant	Exon 6 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.1441A>G		non_coding_transcript_exon_variant	Exon 6 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

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:

AN:

1460634

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000200

AC:

AN:

5008

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111728

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP3+PP2+PM3+PP4 -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Pathogenic:1

Jul 01, 1990

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Jan 20, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

7.7

PrimateAI

Uncertain

0.73

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

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.99

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over