5-1878123-G-A

Position:

• chr5-1878123-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016358.3(IRX4):​c.1406C>T​(p.Pro469Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000717 in 1,394,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IRX4 NM_016358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32955402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX4	NM_016358.3	c.1406C>T	p.Pro469Leu	missense_variant	5/5	ENST00000231357.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX4	ENST00000231357.7	c.1406C>T	p.Pro469Leu	missense_variant	5/5	1	NM_016358.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.085
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	2.0	M;M;.;.;M
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N;N;.;.;N
REVEL	Benign	0.067
Sift	Uncertain	0.013	D;D;.;.;D
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.42	B;B;.;.;B
Vest4		0.30
MutPred		0.35		Gain of catalytic residue at P469 (P = 0.0213);Gain of catalytic residue at P469 (P = 0.0213);.;.;Gain of catalytic residue at P469 (P = 0.0213);
MVP		0.85
MPC		0.81
ClinPred		0.87	D
GERP RS		3.4
Varity_R		0.12
gMVP		0.16

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: rs1211071129; hg19: chr5-1878237;