5-1878571-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016358.3(IRX4):c.958C>A(p.Leu320Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 1.52

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25115222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX4	NM_016358.3	c.958C>A	p.Leu320Met	missense_variant	5/5	ENST00000231357.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX4	ENST00000231357.7	c.958C>A	p.Leu320Met	missense_variant	5/5	1	NM_016358.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394618 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 688024

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Jan 24, 2024

The c.958C>A (p.L320M) alteration is located in exon 5 (coding exon 5) of the IRX4 gene. This alteration results from a C to A substitution at nucleotide position 958, causing the leucine (L) at amino acid position 320 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.;.;T
Eigen	Benign	0.066
Eigen_PC	Benign	-0.0075
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M;M;.;.;M
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.56	N;N;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.079	T;T;.;.;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.94	P;P;.;.;P
Vest4		0.25
MutPred		0.39		Gain of catalytic residue at L320 (P = 0.1027);Gain of catalytic residue at L320 (P = 0.1027);.;.;Gain of catalytic residue at L320 (P = 0.1027);
MVP		0.80
MPC		0.65
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.099
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: rs943412541; hg19: chr5-1878685;