rs2232376

Variant names:

• chr5-1880777-C-T
• rs2232376
• NM_016358.3:c.355G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-1880777-C-T
• chr5-1880777-C-G

Variant summary

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

The NM_016358.3(IRX4):​c.355G>A​(p.Ala119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,276 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3015 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27362 hom.)
• Consequence: IRX4 NM_016358.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.73
• Publications: 15 publications found

Genes affected

IRX4 (HGNC:6129): (iroquois homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within heart development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRX4 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• ventricular septal defect 1

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017234981).
• BP6: Variant 5-1880777-C-T is Benign according to our data. Variant chr5-1880777-C-T is described in ClinVar as Benign. ClinVar VariationId is 1280723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016358.3. 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
	IRX4	NM_016358.3	MANE Select	c.355G>A	p.Ala119Thr	missense	Exon 3 of 5	NP_057442.1	P78413-1
	IRX4	NM_001278633.1		c.355G>A	p.Ala119Thr	missense	Exon 4 of 7	NP_001265562.1	P78413-2
	IRX4	NM_001278635.2		c.355G>A	p.Ala119Thr	missense	Exon 4 of 7	NP_001265564.1	P78413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX4	ENST00000231357.7	TSL:1 MANE Select	c.355G>A	p.Ala119Thr	missense	Exon 3 of 5	ENSP00000231357.2	P78413-1
	IRX4	ENST00000505790.5	TSL:1	c.355G>A	p.Ala119Thr	missense	Exon 4 of 6	ENSP00000423161.1	P78413-1
	IRX4	ENST00000513692.5	TSL:1	c.355G>A	p.Ala119Thr	missense	Exon 4 of 6	ENSP00000424235.1	P78413-1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29502 AN: 151854 Hom.: 3001 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.00600

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.167 AC: 41884 AN: 251104 AF XY: 0.166

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.00729

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.188 AC: 274538 AN: 1461306 Hom.: 27362 Cov.: 33 AF XY: 0.185 AC XY: 134771 AN XY: 726986

African (AFR) AF: 0.231 AC: 7728 AN: 33470

American (AMR) AF: 0.115 AC: 5149 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7548 AN: 26130

East Asian (EAS) AF: 0.00715 AC: 284 AN: 39700

South Asian (SAS) AF: 0.0967 AC: 8340 AN: 86254

European-Finnish (FIN) AF: 0.187 AC: 9945 AN: 53114

Middle Eastern (MID) AF: 0.243 AC: 1400 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 222999 AN: 1111776

Other (OTH) AF: 0.185 AC: 11145 AN: 60376

GnomAD4 genome AF: 0.194 AC: 29541 AN: 151970 Hom.: 3015 Cov.: 31 AF XY: 0.191 AC XY: 14221 AN XY: 74300

African (AFR) AF: 0.227 AC: 9412 AN: 41390

American (AMR) AF: 0.149 AC: 2282 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1031 AN: 3464

East Asian (EAS) AF: 0.00601 AC: 31 AN: 5156

South Asian (SAS) AF: 0.0861 AC: 414 AN: 4810

European-Finnish (FIN) AF: 0.190 AC: 2011 AN: 10588

Middle Eastern (MID) AF: 0.210 AC: 61 AN: 290

European-Non Finnish (NFE) AF: 0.203 AC: 13802 AN: 67976

Other (OTH) AF: 0.195 AC: 411 AN: 2106

Alfa AF: 0.200 Hom.: 12984

Bravo AF: 0.194

TwinsUK AF: 0.187 AC: 693

ALSPAC AF: 0.189 AC: 727

ESP6500AA AF: 0.230 AC: 1014

ESP6500EA AF: 0.203 AC: 1742

ExAC AF: 0.166 AC: 20105

Asia WGS AF: 0.0650 AC: 226 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.212

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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.074
Sift	Benign	0.58	T
Sift4G	Benign	0.45	T
Polyphen		0.58	P
Vest4		0.31
MPC		0.59
ClinPred		0.013	T
GERP RS		4.0
Varity_R		0.093
gMVP		0.70
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: rs2232376; hg19: chr5-1880891; COSMIC: COSV107222988; COSMIC: COSV107222988;