NM_001379150.1:c.3766+3C>A

Variant names:

• chrX-108732576-G-T
• rs28473027
• NM_001379150.1:c.3766+3C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379150.1(IRS4):​c.3766+3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,208,331 control chromosomes in the GnomAD database, including 200 homozygotes. There are 1,564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (109 hom., 748 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (91 hom. 816 hem.)
• Consequence: IRS4 NM_001379150.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.100
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-108732576-G-T is Benign according to our data. Variant chrX-108732576-G-T is described in ClinVar as Benign. ClinVar VariationId is 777818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

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.3766+3C>A		splice_region intron	N/A	NP_001366079.1	A0A804CF45
	IRS4	NM_003604.2		c.3769C>A	p.Arg1257Arg	synonymous	Exon 1 of 1	NP_003595.1	O14654
	IRS4	NM_001440817.1		c.3766+3C>A		splice_region intron	N/A	NP_001427746.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS4	ENST00000372129.4	TSL:6 MANE Select	c.3766+3C>A		splice_region intron	N/A	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3769C>A	p.Arg1257Arg	synonymous	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 2840 AN: 111677 Hom.: 109 Cov.: 23

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0179

GnomAD2 exomes AF: 0.00742 AC: 1362 AN: 183465 AF XY: 0.00473

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00274 AC: 3004 AN: 1096604 Hom.: 91 Cov.: 30 AF XY: 0.00225 AC XY: 816 AN XY: 361980

African (AFR) AF: 0.0936 AC: 2469 AN: 26366

American (AMR) AF: 0.00500 AC: 176 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.000333 AC: 18 AN: 54105

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4127

European-Non Finnish (NFE) AF: 0.0000607 AC: 51 AN: 840664

Other (OTH) AF: 0.00617 AC: 284 AN: 46042

GnomAD4 genome AF: 0.0254 AC: 2839 AN: 111727 Hom.: 109 Cov.: 23 AF XY: 0.0220 AC XY: 748 AN XY: 33933

African (AFR) AF: 0.0872 AC: 2670 AN: 30631

American (AMR) AF: 0.0122 AC: 130 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.000750 AC: 2 AN: 2668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53195

Other (OTH) AF: 0.0177 AC: 27 AN: 1526

Alfa AF: 0.00366 Hom.: 20

Bravo AF: 0.0295

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.5
DANN	Benign	0.89
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28473027; hg19: chrX-107975806;