X-108733240-G-A

Variant names:

• chrX-108733240-G-A
• rs143866591
• NM_001379150.1:c.3105C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001379150.1(IRS4):​c.3105C>T​(p.Ala1035Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,210,095 control chromosomes in the GnomAD database, including 26 homozygotes. There are 666 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., 323 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (13 hom. 343 hem.)
• Consequence: IRS4 NM_001379150.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.706
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-108733240-G-A is Benign according to our data. Variant chrX-108733240-G-A is described in ClinVar as Benign. ClinVar VariationId is 716036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.706 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1183/111863) while in subpopulation AFR AF = 0.0368 (1134/30789). AF 95% confidence interval is 0.0351. There are 13 homozygotes in GnomAd4. There are 323 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.3105C>T	p.Ala1035Ala	synonymous	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3105C>T	p.Ala1035Ala	synonymous	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3105C>T	p.Ala1035Ala	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.3105C>T	p.Ala1035Ala	synonymous	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3105C>T	p.Ala1035Ala	synonymous	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1177 AN: 111810 Hom.: 13 Cov.: 23

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00349

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00532

GnomAD2 exomes AF: 0.00312 AC: 572 AN: 183503 AF XY: 0.00230

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00115 AC: 1268 AN: 1098232 Hom.: 13 Cov.: 32 AF XY: 0.000943 AC XY: 343 AN XY: 363588

African (AFR) AF: 0.0392 AC: 1035 AN: 26400

American (AMR) AF: 0.00219 AC: 77 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54146

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40532

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4136

European-Non Finnish (NFE) AF: 0.0000641 AC: 54 AN: 842125

Other (OTH) AF: 0.00204 AC: 94 AN: 46096

GnomAD4 genome AF: 0.0106 AC: 1183 AN: 111863 Hom.: 13 Cov.: 23 AF XY: 0.00949 AC XY: 323 AN XY: 34033

African (AFR) AF: 0.0368 AC: 1134 AN: 30789

American (AMR) AF: 0.00348 AC: 37 AN: 10628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.000375 AC: 1 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53131

Other (OTH) AF: 0.00525 AC: 8 AN: 1524

Alfa AF: 0.00491 Hom.: 24

Bravo AF: 0.0123

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: 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	-0.67
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs143866591; hg19: chrX-107976470;