X-108732928-C-A

Variant names:

• chrX-108732928-C-A
• rs777547295
• NM_001379150.1:c.3417G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001379150.1(IRS4):​c.3417G>T​(p.Ala1139Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,180,883 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000036 (0 hom. 20 hem.)
• Consequence: IRS4 NM_001379150.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.279
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-108732928-C-A is Benign according to our data. Variant chrX-108732928-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2661172.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.279 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 20 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.3417G>T	p.Ala1139Ala	synonymous	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3417G>T	p.Ala1139Ala	synonymous	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3417G>T	p.Ala1139Ala	synonymous	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.3417G>T	p.Ala1139Ala	synonymous	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3417G>T	p.Ala1139Ala	synonymous	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112216 Hom.: 0 Cov.: 24

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000639 AC: 10 AN: 156609 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000262

GnomAD4 exome AF: 0.0000356 AC: 38 AN: 1068616 Hom.: 0 Cov.: 31 AF XY: 0.0000581 AC XY: 20 AN XY: 344004

African (AFR) AF: 0.00 AC: 0 AN: 25461

American (AMR) AF: 0.00 AC: 0 AN: 32324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17932

East Asian (EAS) AF: 0.00 AC: 0 AN: 29776

South Asian (SAS) AF: 0.00 AC: 0 AN: 50377

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4005

European-Non Finnish (NFE) AF: 0.0000424 AC: 35 AN: 825981

Other (OTH) AF: 0.0000670 AC: 3 AN: 44754

GnomAD4 genome AF: 0.0000624 AC: 7 AN: 112267 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34447

African (AFR) AF: 0.00 AC: 0 AN: 30961

American (AMR) AF: 0.00 AC: 0 AN: 10720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53170

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.2
DANN	Benign	0.72
PhyloP100		-0.28
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: rs777547295; hg19: chrX-107976158;