5-1878093-T-A

Position:

• chr5-1878093-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016358.3(IRX4):​c.1436A>T​(p.Asn479Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: IRX4 NM_016358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX4	NM_016358.3	c.1436A>T	p.Asn479Ile	missense_variant	5/5	ENST00000231357.7	NP_057442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX4	ENST00000231357.7	c.1436A>T	p.Asn479Ile	missense_variant	5/5	1	NM_016358.3	ENSP00000231357.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

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

Sep 27, 2024

The c.1436A>T (p.N479I) alteration is located in exon 5 (coding exon 5) of the IRX4 gene. This alteration results from a A to T substitution at nucleotide position 1436, causing the asparagine (N) at amino acid position 479 to be replaced by an isoleucine (I). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;T;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	.;T;.;T;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	2.0	M;M;.;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D;D;.;.;D
REVEL	Benign	0.065
Sift	Uncertain	0.0020	D;D;.;.;D
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		0.43	B;B;.;.;B
Vest4		0.60
MutPred		0.33		Loss of disorder (P = 0.0196);Loss of disorder (P = 0.0196);.;.;Loss of disorder (P = 0.0196);
MVP		0.86
MPC		1.2
ClinPred		0.82	D
GERP RS		2.4
Varity_R		0.28
gMVP		0.40

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: chr5-1878207;