X-108732921-C-T

Variant names:

• chrX-108732921-C-T
• rs2068914139
• NM_001379150.1:c.3424G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379150.1(IRS4):​c.3424G>A​(p.Ala1142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000938 in 1,066,493 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. 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. A1142S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

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)

ACMG classification

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=0.27497852).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS4	NM_001379150.1	MANE Select	c.3424G>A	p.Ala1142Thr	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3424G>A	p.Ala1142Thr	missense	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3424G>A	p.Ala1142Thr	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>A	p.Ala1142Thr	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3424G>A	p.Ala1142Thr	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.38e-7 AC: 1 AN: 1066493 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 1 AN XY: 343091

African (AFR) AF: 0.00 AC: 0 AN: 25414

American (AMR) AF: 0.00 AC: 0 AN: 32103

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17729

East Asian (EAS) AF: 0.00 AC: 0 AN: 29783

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49863

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37899

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3995

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825059

Other (OTH) AF: 0.00 AC: 0 AN: 44648

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.11
Sift	Benign	0.059	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.24
MutPred		0.20		Gain of glycosylation at A1142 (P = 0.0044)
MVP		0.29
MPC		0.48
ClinPred		0.53	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.18
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2068914139; hg19: chrX-107976151; COSMIC: COSV64536035; COSMIC: COSV64536035;