5-1878251-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016358.3(IRX4):c.1278G>T(p.Arg426Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: IRX4 NM_016358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.578

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX4	NM_016358.3	c.1278G>T	p.Arg426Ser	missense_variant	5/5	ENST00000231357.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX4	ENST00000231357.7	c.1278G>T	p.Arg426Ser	missense_variant	5/5	1	NM_016358.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.1278G>T (p.R426S) alteration is located in exon 5 (coding exon 5) of the IRX4 gene. This alteration results from a G to T substitution at nucleotide position 1278, causing the arginine (R) at amino acid position 426 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;T
Eigen	Benign	0.080
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M;M;.;.;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.5	N;N;.;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.064	T;T;.;.;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.82	P;P;.;.;P
Vest4		0.61
MutPred		0.47		Gain of glycosylation at R426 (P = 0.0436);Gain of glycosylation at R426 (P = 0.0436);.;.;Gain of glycosylation at R426 (P = 0.0436);
MVP		0.86
MPC		1.4
ClinPred		0.87	D
GERP RS		3.4
Varity_R		0.27
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1878365;