5-1878407-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_016358.3(IRX4):c.1122A>G(p.Thr374=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,525,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: IRX4 NM_016358.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-1878407-T-C is Benign according to our data. Variant chr5-1878407-T-C is described in ClinVar as [Benign]. Clinvar id is 776036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX4	NM_016358.3	c.1122A>G	p.Thr374=	synonymous_variant	5/5	ENST00000231357.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX4	ENST00000231357.7	c.1122A>G	p.Thr374=	synonymous_variant	5/5	1	NM_016358.3	P1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 200 AN: 151996 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000243 AC: 30 AN: 123494 Hom.: 0 AF XY: 0.000224 AC XY: 15 AN XY: 67008

Gnomad AFR exome AF: 0.00347

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000496

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 149 AN: 1373110 Hom.: 1 Cov.: 33 AF XY: 0.0000887 AC XY: 60 AN XY: 676266

Gnomad4 AFR exome AF: 0.00381

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.000244

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152112 Hom.: 0 Cov.: 34 AF XY: 0.00129 AC XY: 96 AN XY: 74370

Gnomad4 AFR AF: 0.00444

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000782 Hom.: 0

Bravo AF: 0.00145

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.84
Dann	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs552977211; hg19: chr5-1878521;