16-54931400-G-C

Variant names:

• chr16-54931400-G-C
• rs768213705
• NM_005853.6:c.202G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005853.6(IRX5):​c.202G>C​(p.Gly68Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41375202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX5	NM_005853.6	c.202G>C	p.Gly68Arg	missense_variant	Exon 1 of 3	ENST00000394636.9	NP_005844.4
IRX5	NM_001252197.1	c.202G>C	p.Gly68Arg	missense_variant	Exon 1 of 3		NP_001239126.1
IRX5	XM_011522809.1	c.-771G>C		upstream_gene_variant			XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRX5	ENST00000394636.9	c.202G>C	p.Gly68Arg	missense_variant	Exon 1 of 3	3	NM_005853.6	ENSP00000378132.4
IRX5	ENST00000320990.9	c.202G>C	p.Gly68Arg	missense_variant	Exon 1 of 3	1		ENSP00000316250.5
IRX5	ENST00000560154.5	c.202G>C	p.Gly68Arg	missense_variant	Exon 1 of 3	5		ENSP00000453660.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000448 AC: 1 AN: 222986 Hom.: 0 AF XY: 0.00000803 AC XY: 1 AN XY: 124484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000992

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445076 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 719110

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: 9.01e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;D;D;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.46	N;.;.;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.032	D;T;T;D
Polyphen		0.63	P;.;D;.
Vest4		0.55
MutPred		0.24		Gain of methylation at G68 (P = 0.0394);Gain of methylation at G68 (P = 0.0394);Gain of methylation at G68 (P = 0.0394);Gain of methylation at G68 (P = 0.0394);
MVP		0.64
ClinPred		0.75	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.75

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: rs768213705; hg19: chr16-54965312;