chrX-108732657-C-A

Variant names:

• chrX-108732657-C-A
• rs28546943
• NM_001379150.1:c.3688G>T

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.3688G>T​(p.Asp1230Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,209,955 control chromosomes in the GnomAD database, including 199 homozygotes. There are 1,566 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (108 hom., 747 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (91 hom. 819 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.830
• Publications: 2 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 (MetaRNN=0.0016138852).
• BP6: Variant X-108732657-C-A is Benign according to our data. Variant chrX-108732657-C-A is described in ClinVar as Benign. ClinVar VariationId is 777819.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.3688G>T	p.Asp1230Tyr	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.3688G>T	p.Asp1230Tyr	missense	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.3688G>T	p.Asp1230Tyr	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.3688G>T	p.Asp1230Tyr	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3688G>T	p.Asp1230Tyr	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 2840 AN: 111662 Hom.: 108 Cov.: 23

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00742 AC: 1362 AN: 183509 AF XY: 0.00470

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.00438

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: 3008 AN: 1098239 Hom.: 91 Cov.: 31 AF XY: 0.00225 AC XY: 819 AN XY: 363595

African (AFR) AF: 0.0937 AC: 2473 AN: 26401

American (AMR) AF: 0.00500 AC: 176 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.000332 AC: 18 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4137

European-Non Finnish (NFE) AF: 0.0000606 AC: 51 AN: 842126

Other (OTH) AF: 0.00616 AC: 284 AN: 46097

GnomAD4 genome AF: 0.0254 AC: 2839 AN: 111716 Hom.: 108 Cov.: 23 AF XY: 0.0220 AC XY: 747 AN XY: 33896

African (AFR) AF: 0.0872 AC: 2676 AN: 30692

American (AMR) AF: 0.0119 AC: 127 AN: 10630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3521

South Asian (SAS) AF: 0.000377 AC: 1 AN: 2650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6020

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

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53142

Other (OTH) AF: 0.0165 AC: 25 AN: 1517

Alfa AF: 0.0104 Hom.: 535

Bravo AF: 0.0295

ESP6500AA AF: 0.0900 AC: 345

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00814 AC: 988

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.83
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.12
Sift	Benign	0.34	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.095
MVP		0.40
MPC		0.61
ClinPred		0.060	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.20
Mutation Taster		=96/4	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: rs28546943; hg19: chrX-107975887;