chr16-55327359-G-A

Position:

• chr16-55327359-G-A

Variant summary

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

The NM_024335.3(IRX6):​c.367G>A​(p.Ala123Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IRX6 NM_024335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

Genes affected

IRX6 (HGNC:14675): (iroquois homeobox 6) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor 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, DNA-templated. Predicted to act upstream of or within detection of visible light; negative regulation of transcription, DNA-templated; and retina morphogenesis in camera-type eye. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRX6 (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=0.25155205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX6	NM_024335.3	c.367G>A	p.Ala123Thr	missense_variant	3/6	ENST00000290552.8	NP_077311.2
IRX6	XM_005256137.4	c.367G>A	p.Ala123Thr	missense_variant	3/6		XP_005256194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX6	ENST00000290552.8	c.367G>A	p.Ala123Thr	missense_variant	3/6	1	NM_024335.3	ENSP00000290552.8
IRX6	ENST00000558315.1	n.593G>A		non_coding_transcript_exon_variant	4/5	1
ENSG00000259283	ENST00000558730.2	n.88+6142C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727204

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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 05, 2023

The c.367G>A (p.A123T) alteration is located in exon 3 (coding exon 3) of the IRX6 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the alanine (A) at amino acid position 123 to be replaced by a threonine (T). 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	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.0091	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.23
Sift	Benign	0.074	T
Sift4G	Benign	0.14	T
Polyphen		0.60	P
Vest4		0.23
MutPred		0.27		Gain of glycosylation at A123 (P = 0.012);
MVP		0.93
MPC		0.091
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.16
gMVP		0.69

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: rs1049450659; hg19: chr16-55361271; COSMIC: COSV51862456; COSMIC: COSV51862456;