chr16-54285096-G-A

Position:

• chr16-54285096-G-A

Variant summary

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

The NM_024336.3(IRX3):​c.785C>T​(p.Ala262Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IRX3 NM_024336.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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 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=0.16208538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX3	NM_024336.3	c.785C>T	p.Ala262Val	missense_variant	2/4	ENST00000329734.4	NP_077312.2
IRX3	XM_005256139.4	c.785C>T	p.Ala262Val	missense_variant	2/4		XP_005256196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX3	ENST00000329734.4	c.785C>T	p.Ala262Val	missense_variant	2/4	1	NM_024336.3	ENSP00000331608.3
IRX3	ENST00000558054.1	c.72+688C>T		intron_variant		2		ENSP00000463991.1
IRX3	ENST00000558180.2	n.564C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

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.785C>T (p.A262V) 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 785, causing the alanine (A) at amino acid position 262 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	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.091	B
Vest4		0.17
MutPred		0.14		Gain of relative solvent accessibility (P = 0.09);
MVP		0.37
ClinPred		0.82	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.12

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: chr16-54319008;