16-54932746-C-A

Position:

• chr16-54932746-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005853.6(IRX5):​c.498C>A​(p.Asn166Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.31

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 16-54932746-C-A is Pathogenic according to our data. Variant chr16-54932746-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 31910.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-54932746-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX5	NM_005853.6	c.498C>A	p.Asn166Lys	missense_variant	2/3	ENST00000394636.9	NP_005844.4
IRX5	NM_001252197.1	c.498C>A	p.Asn166Lys	missense_variant	2/3		NP_001239126.1
IRX5	XM_011522809.1	c.288C>A	p.Asn96Lys	missense_variant	2/3		XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX5	ENST00000394636.9	c.498C>A	p.Asn166Lys	missense_variant	2/3	3	NM_005853.6	ENSP00000378132	A1
IRX5	ENST00000320990.9	c.498C>A	p.Asn166Lys	missense_variant	2/3	1		ENSP00000316250	P4
IRX5	ENST00000558597.1	n.675C>A		non_coding_transcript_exon_variant	1/2	1
IRX5	ENST00000560154.5	c.405+537C>A		intron_variant		5		ENSP00000453660

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Craniofacial dysplasia - osteopenia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 13, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.79		Gain of methylation at N166 (P = 0.0059);Gain of methylation at N166 (P = 0.0059);
MVP		0.98
ClinPred		1.0	D
GERP RS		1.1
Varity_R		0.96
gMVP		1.0

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: rs786200931; hg19: chr16-54966658;