X-108736172-G-C

Position:

• chrX-108736172-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379150.1(IRS4):​c.173C>G​(p.Thr58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

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-AS1 (HGNC:55650): (IRS4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08708212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.173C>G	p.Thr58Arg	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2	c.173C>G	p.Thr58Arg	missense_variant	1/1
IRS4	XM_011531061.2	c.173C>G	p.Thr58Arg	missense_variant	1/3
IRS4	XM_006724713.4	c.173C>G	p.Thr58Arg	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.173C>G	p.Thr58Arg	missense_variant	1/2		NM_001379150.1	A2
IRS4-AS1	ENST00000668534.1	n.82G>C		non_coding_transcript_exon_variant	1/3
IRS4	ENST00000564206.2	c.173C>G	p.Thr58Arg	missense_variant	1/1			P5
IRS4-AS1	ENST00000608811.1	n.162G>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.173C>G (p.T58R) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to G substitution at nucleotide position 173, causing the threonine (T) at amino acid position 58 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.026
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.20	B
Vest4		0.12
MutPred		0.23		Loss of glycosylation at T58 (P = 0.0147);
MVP		0.11
MPC		1.3
ClinPred		0.28	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107979402;