Genetic Variant NM_001379150.1:c.3766+3C>A (chrX-108732576-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379150.1(IRS4):c.3766+3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,208,331 control chromosomes in the GnomAD database, including 200 homozygotes. There are 1,564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 109 hom., 748 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 91 hom. 816 hem. )

Consequence

IRS4
NM_001379150.1 splice_region, intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.100

Variant links:

Genes affected

IRS4 (HGNC:6128): (insulin receptor substrate 4) IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]

IRS4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant X-108732576-G-T is Benign according to our data. Variant chrX-108732576-G-T is described in ClinVar as [Benign]. Clinvar id is 777818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108732576-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.3766+3C>A		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 link	c.3769C>A	p.Arg1257Arg	synonymous_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_011531061.2 link	c.3766+3C>A		splice_region_variant, intron_variant	Intron 1 of 2		XP_011529363.1
IRS4	XM_006724713.4 link	c.3766+3C>A		splice_region_variant, intron_variant	Intron 1 of 1		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4 link	c.3766+3C>A		splice_region_variant, intron_variant	Intron 1 of 1	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 link	c.3769C>A	p.Arg1257Arg	synonymous_variant	Exon 1 of 1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

2840

AN:

111677

Hom.:

109

Cov.:

AF XY:

0.0221

AC XY:

749

AN XY:

33873

show subpopulations

Gnomad AFR

AF:

0.0874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000747

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.0179

GnomAD3 exomes

AF:

0.00742

AC:

1362

AN:

183465

Hom.:

AF XY:

0.00473

AC XY:

321

AN XY:

67905

show subpopulations

Gnomad AFR exome

AF:

0.0925

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00274

AC:

3004

AN:

1096604

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

816

AN XY:

361980

show subpopulations

Gnomad4 AFR exome

AF:

0.0936

Gnomad4 AMR exome

AF:

0.00500

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000333

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000607

Gnomad4 OTH exome

AF:

0.00617

GnomAD4 genome

AF:

0.0254

AC:

2839

AN:

111727

Hom.:

109

Cov.:

AF XY:

0.0220

AC XY:

748

AN XY:

33933

show subpopulations

Gnomad4 AFR

AF:

0.0872

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000750

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.0177

Alfa

AF:

0.00366

Hom.:

Bravo

AF:

0.0295

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.51

CADD

Benign

8.5

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over