NM_001379150.1:c.3050T>C

Variant names:

• chrX-108733295-A-G
• rs1262166840
• NM_001379150.1:c.3050T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001379150.1(IRS4):​c.3050T>C​(p.Ile1017Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,209,968 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 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.3050T>C	p.Ile1017Thr	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3050T>C	p.Ile1017Thr	missense	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3050T>C	p.Ile1017Thr	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.3050T>C	p.Ile1017Thr	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3050T>C	p.Ile1017Thr	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111809 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183491 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00000546 AC: 6 AN: 1098159 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363513

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

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

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842051

Other (OTH) AF: 0.00 AC: 0 AN: 46092

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111809 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33991

African (AFR) AF: 0.00 AC: 0 AN: 30727

American (AMR) AF: 0.00 AC: 0 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53132

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.24
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.22
Sift	Benign	0.45	T
Sift4G	Benign	0.36	T
Polyphen		0.15	B
Vest4		0.65
MutPred		0.68		Loss of stability (P = 0.0222)
MVP		0.89
MPC		0.63
ClinPred		0.87	D
GERP RS		4.2
Varity_R		0.094
gMVP		0.42
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: rs1262166840; hg19: chrX-107976525;