16-54931398-A-G

Variant names:

• chr16-54931398-A-G
• rs1285463893
• NM_005853.6:c.200A>G

Variant summary

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

The NM_005853.6(IRX5):​c.200A>G​(p.Tyr67Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,445,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

Genes affected

IRX5 (HGNC:14361): (iroquois homeobox 5) This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

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, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX5	NM_005853.6	c.200A>G	p.Tyr67Cys	missense_variant	Exon 1 of 3	ENST00000394636.9	NP_005844.4
IRX5	NM_001252197.1	c.200A>G	p.Tyr67Cys	missense_variant	Exon 1 of 3		NP_001239126.1
IRX5	XM_011522809.1	c.-773A>G		upstream_gene_variant			XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRX5	ENST00000394636.9	c.200A>G	p.Tyr67Cys	missense_variant	Exon 1 of 3	3	NM_005853.6	ENSP00000378132.4
IRX5	ENST00000320990.9	c.200A>G	p.Tyr67Cys	missense_variant	Exon 1 of 3	1		ENSP00000316250.5
IRX5	ENST00000560154.5	c.200A>G	p.Tyr67Cys	missense_variant	Exon 1 of 3	5		ENSP00000453660.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000623 AC: 9 AN: 1445672 Hom.: 0 Cov.: 32 AF XY: 0.00000695 AC XY: 5 AN XY: 719454

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: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200A>G (p.Y67C) alteration is located in exon 1 (coding exon 1) of the IRX5 gene. This alteration results from a A to G substitution at nucleotide position 200, causing the tyrosine (Y) at amino acid position 67 to be replaced by a cysteine (C). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	L;.;.;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.5	D;D;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.62
MutPred		0.30		Loss of solvent accessibility (P = 0.0089);Loss of solvent accessibility (P = 0.0089);Loss of solvent accessibility (P = 0.0089);Loss of solvent accessibility (P = 0.0089);
MVP		0.75
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.68
gMVP		0.87

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: rs1285463893; hg19: chr16-54965310;