chr5-1877166-A-C

Variant names:

• chr5-1877166-A-C
• rs4975709
• NM_016358.3:c.*803T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016358.3(IRX4):​c.*803T>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,158 control chromosomes in the GnomAD database, including 5,840 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5840 hom., cov: 34)
• Consequence: IRX4 NM_016358.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.742
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX4	NM_016358.3	c.*803T>G		downstream_gene_variant		ENST00000231357.7	NP_057442.1
IRX4	NM_001278635.2	c.*803T>G		downstream_gene_variant			NP_001265564.1
IRX4	NM_001278634.2	c.*803T>G		downstream_gene_variant			NP_001265563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRX4	ENST00000231357.7	c.*803T>G		downstream_gene_variant		1	NM_016358.3	ENSP00000231357.2

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41463 AN: 152040 Hom.: 5834 Cov.: 34

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.273 AC: 41495 AN: 152158 Hom.: 5840 Cov.: 34 AF XY: 0.272 AC XY: 20237 AN XY: 74390

African (AFR) AF: 0.325 AC: 13486 AN: 41484

American (AMR) AF: 0.322 AC: 4931 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 810 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1583 AN: 5176

South Asian (SAS) AF: 0.256 AC: 1235 AN: 4830

European-Finnish (FIN) AF: 0.223 AC: 2360 AN: 10586

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16174 AN: 67990

Other (OTH) AF: 0.268 AC: 565 AN: 2112

Alfa AF: 0.248 Hom.: 19090

Bravo AF: 0.283

Asia WGS AF: 0.273 AC: 947 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.56
PhyloP100		-0.74

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4975709; hg19: chr5-1877280;