dbSNP rs17847227: IRS4:p.Ala1158Ser (chrX-108732873-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001379150.1(IRS4):c.3472G>T(p.Ala1158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000948 in 1,054,944 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1158T) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.5e-7 ( 0 hom. 0 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.657

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypothyroidism, congenital, nongoitrous, 9
Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

IRS4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32822698).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379150.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRS4	NM_001379150.1	MANE Select	c.3472G>T	p.Ala1158Ser	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
IRS4	NM_001440817.1		c.3472G>T	p.Ala1158Ser	missense	Exon 1 of 3	NP_001427746.1
IRS4	NM_003604.2		c.3472G>T	p.Ala1158Ser	missense	Exon 1 of 1	NP_003595.1	O14654

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS4	ENST00000372129.4	TSL:6 MANE Select	c.3472G>T	p.Ala1158Ser	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3472G>T	p.Ala1158Ser	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.48e-7

AC:

AN:

1054944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

339238

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24794

American (AMR)

AF:

0.00

AC:

AN:

29244

Ashkenazi Jewish (ASJ)

AF:

0.0000599

AC:

AN:

16689

East Asian (EAS)

AF:

0.00

AC:

AN:

29759

South Asian (SAS)

AF:

0.00

AC:

AN:

47442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3943

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820744

Other (OTH)

AF:

0.00

AC:

AN:

44113

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.66

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.63

REVEL

Benign

0.087

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.049

Polyphen

0.95

Vest4

0.22

MutPred

0.23

Gain of glycosylation at A1158 (P = 0.0335)

MVP

0.30

MPC

0.45

ClinPred

0.74

GERP RS

3.8

Varity_R

0.14

gMVP

0.11

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over