NM_000208.4:c.974+89C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000208.4(INSR):c.974+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,174,158 control chromosomes in the GnomAD database, including 20,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3267 hom., cov: 29)

Exomes 𝑓: 0.18 ( 17177 hom. )

Consequence

INSR
NM_000208.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.756

Publications

10 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-7184227-G-A is Benign according to our data. Variant chr19-7184227-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
INSR	NM_000208.4 link	c.974+89C>T	intron_variant	Intron 3 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 link	c.974+89C>T	intron_variant	Intron 3 of 20		NP_001073285.1
INSR	XM_011527988.3 link	c.974+89C>T	intron_variant	Intron 3 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.974+89C>T	intron_variant	Intron 3 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
INSR	ENST00000302850.10 link	c.974+89C>T	intron_variant	Intron 3 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9 link	c.974+89C>T	intron_variant	Intron 3 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1 link	n.949+89C>T	intron_variant	Intron 3 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30745

AN:

151476

Hom.:

3252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.219

GnomAD4 exome

AF:

0.179

AC:

183441

AN:

1022564

Hom.:

17177

AF XY:

0.180

AC XY:

93734

AN XY:

520676

show subpopulations

African (AFR)

AF:

0.261

AC:

6498

AN:

24928

American (AMR)

AF:

0.233

AC:

8808

AN:

37814

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

4483

AN:

22834

East Asian (EAS)

AF:

0.128

AC:

4641

AN:

36382

South Asian (SAS)

AF:

0.219

AC:

16082

AN:

73482

European-Finnish (FIN)

AF:

0.204

AC:

8831

AN:

43376

Middle Eastern (MID)

AF:

0.174

AC:

590

AN:

3396

European-Non Finnish (NFE)

AF:

0.170

AC:

125032

AN:

734596

Other (OTH)

AF:

0.185

AC:

8476

AN:

45756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

7478

14957

22435

29914

37392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3762

7524

11286

15048

18810

<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:

0.203

AC:

30803

AN:

151594

Hom.:

3267

Cov.:

AF XY:

0.206

AC XY:

15233

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.258

AC:

10663

AN:

41302

American (AMR)

AF:

0.211

AC:

3209

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

683

AN:

3468

East Asian (EAS)

AF:

0.118

AC:

610

AN:

5164

South Asian (SAS)

AF:

0.219

AC:

1054

AN:

4806

European-Finnish (FIN)

AF:

0.217

AC:

2276

AN:

10468

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.172

AC:

11709

AN:

67900

Other (OTH)

AF:

0.219

AC:

459

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1111

2223

3334

4446

5557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.192

Hom.:

386

Bravo

AF:

0.205

Asia WGS

AF:

0.188

AC:

653

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.061

(source)

DANN

Benign

0.86

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over