chr16-54284559-G-A

Position:

• chr16-54284559-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024336.3(IRX3):​c.1322C>T​(p.Ala441Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000553 in 1,264,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IRX3 NM_024336.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

IRX3 (HGNC:14360): (iroquois homeobox 3) IRX3 is a member of the Iroquois homeobox gene family (see IRX1; MIM 606197) and plays a role in an early step of neural development (Bellefroid et al., 1998 [PubMed 9427753]). Members of this family appear to play multiple roles during pattern formation of vertebrate embryos (Lewis et al., 1999 [PubMed 10370142]).[supplied by OMIM, Aug 2009]

IRX3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19309512).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX3	NM_024336.3	c.1322C>T	p.Ala441Val	missense_variant	2/4	ENST00000329734.4	NP_077312.2
IRX3	XM_005256139.4	c.1322C>T	p.Ala441Val	missense_variant	2/4		XP_005256196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX3	ENST00000329734.4	c.1322C>T	p.Ala441Val	missense_variant	2/4	1	NM_024336.3	ENSP00000331608.3
IRX3	ENST00000558054.1	c.73-247C>T		intron_variant		2		ENSP00000463991.1
IRX3	ENST00000558180.2	n.1101C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000553 AC: 7 AN: 1264890 Hom.: 0 Cov.: 33 AF XY: 0.00000645 AC XY: 4 AN XY: 620094

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: 0.0000496

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000764

GnomAD4 genome Cov.: 35

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

Jun 28, 2022

The c.1322C>T (p.A441V) alteration is located in exon 2 (coding exon 2) of the IRX3 gene. This alteration results from a C to T substitution at nucleotide position 1322, causing the alanine (A) at amino acid position 441 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.080
Sift	Benign	0.069	T
Sift4G	Benign	0.13	T
Polyphen		0.018	B
Vest4		0.21
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.34
ClinPred		0.52	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.55

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: rs1293662778; hg19: chr16-54318471;