Variant 16-54931374-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005853.6(IRX5):c.176C>A(p.Pro59Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000175 in 1,604,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

IRX5
NM_005853.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.12

Variant links:

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]

IRX5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.24380273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX5	NM_005853.6 link	c.176C>A	p.Pro59Gln	missense_variant	Exon 1 of 3	ENST00000394636.9	NP_005844.4	P78411-1
IRX5	NM_001252197.1 link	c.176C>A	p.Pro59Gln	missense_variant	Exon 1 of 3		NP_001239126.1	P78411-2
IRX5	XM_011522809.1 link	c.-797C>A		upstream_gene_variant			XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRX5	ENST00000394636.9 link	c.176C>A	p.Pro59Gln	missense_variant	Exon 1 of 3	3	NM_005853.6	ENSP00000378132.4	P78411-1
IRX5	ENST00000320990.9 link	c.176C>A	p.Pro59Gln	missense_variant	Exon 1 of 3	1		ENSP00000316250.5	P78411-2
IRX5	ENST00000560154.5 link	c.176C>A	p.Pro59Gln	missense_variant	Exon 1 of 3	5		ENSP00000453660.1	H0YML8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000855

AC:

AN:

234050

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129398

show subpopulations

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:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1451878

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

722602

show subpopulations

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:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176C>A (p.P59Q) alteration is located in exon 1 (coding exon 1) of the IRX5 gene. This alteration results from a C to A substitution at nucleotide position 176, causing the proline (P) at amino acid position 59 to be replaced by a glutamine (Q). 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

0.24

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.056

T;.;T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

T;D;D;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.;.;L

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.42

N;D;.;N

REVEL

Benign

0.18

Sift

Benign

0.32

T;D;.;T

Sift4G

Benign

0.55

T;D;D;T

Polyphen

0.43

B;.;D;.

Vest4

0.34

MVP

0.73

ClinPred

0.84

GERP RS

4.9

Varity_R

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over