16-54932647-C-G

Position:

• chr16-54932647-C-G

Variant summary

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

The NM_005853.6(IRX5):​c.399C>G​(p.Asn133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0140

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX5	NM_005853.6	c.399C>G	p.Asn133Lys	missense_variant	2/3	ENST00000394636.9	NP_005844.4
IRX5	NM_001252197.1	c.399C>G	p.Asn133Lys	missense_variant	2/3		NP_001239126.1
IRX5	XM_011522809.1	c.189C>G	p.Asn63Lys	missense_variant	2/3		XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRX5	ENST00000394636.9	c.399C>G	p.Asn133Lys	missense_variant	2/3	3	NM_005853.6	ENSP00000378132	A1
IRX5	ENST00000320990.9	c.399C>G	p.Asn133Lys	missense_variant	2/3	1		ENSP00000316250	P4
IRX5	ENST00000558597.1	n.576C>G		non_coding_transcript_exon_variant	1/2	1
IRX5	ENST00000560154.5	c.405+438C>G		intron_variant		5		ENSP00000453660

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.399C>G (p.N133K) alteration is located in exon 2 (coding exon 2) of the IRX5 gene. This alteration results from a C to G substitution at nucleotide position 399, causing the asparagine (N) at amino acid position 133 to be replaced by a lysine (K). 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	0.99
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.96	D;.
Vest4		0.80
MutPred		0.50		Gain of methylation at N133 (P = 0.0068);Gain of methylation at N133 (P = 0.0068);
MVP		0.79
ClinPred		0.99	D
GERP RS		-3.1
Varity_R		0.47
gMVP		0.96

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: chr16-54966559;