chrX-108732669-G-T

Variant names:

• chrX-108732669-G-T
• rs759723131
• NM_001379150.1:c.3676C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001379150.1(IRS4):​c.3676C>A​(p.Pro1226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,098,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 6 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06737661).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

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.3676C>A	p.Pro1226Thr	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3676C>A	p.Pro1226Thr	missense	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3676C>A	p.Pro1226Thr	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.3676C>A	p.Pro1226Thr	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3676C>A	p.Pro1226Thr	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.000136 AC: 25 AN: 183499 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1098213 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 363571

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.000710 AC: 25 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842104

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.61	P
Vest4		0.14
MutPred		0.20		Gain of phosphorylation at P1226 (P = 0.0019)
MVP		0.24
MPC		0.55
ClinPred		0.27	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.12
Mutation Taster		=100/0	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: rs759723131; hg19: chrX-107975899; COSMIC: COSV64535677; COSMIC: COSV64535677;