Genetic Variant NM_001379150.1:c.3424G>T (chrX-108732921-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.3424G>T(p.Ala1142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,066,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

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=0.29924816).

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.3424G>T	p.Ala1142Ser	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
IRS4	NM_001440817.1		c.3424G>T	p.Ala1142Ser	missense	Exon 1 of 3	NP_001427746.1
IRS4	NM_003604.2		c.3424G>T	p.Ala1142Ser	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.3424G>T	p.Ala1142Ser	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3424G>T	p.Ala1142Ser	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000188

AC:

AN:

1066495

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

343093

show subpopulations

African (AFR)

AF:

0.0000787

AC:

AN:

25414

American (AMR)

AF:

0.00

AC:

AN:

32103

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17729

East Asian (EAS)

AF:

0.00

AC:

AN:

29784

South Asian (SAS)

AF:

0.00

AC:

AN:

49863

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3995

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

825059

Other (OTH)

AF:

0.00

AC:

AN:

44648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.19

REVEL

Benign

0.077

Sift

Uncertain

0.015

Sift4G

Uncertain

0.0040

Polyphen

0.85

Vest4

0.24

MutPred

0.15

Gain of glycosylation at A1142 (P = 0.0012)

MVP

0.27

MPC

0.45

ClinPred

0.55

GERP RS

5.3

Varity_R

0.14

gMVP

0.13

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over