16-54931364-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005853.6(IRX5):c.166G>A(p.Ala56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,606,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

IRX5
NM_005853.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.23

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018190354).

BP6

Variant 16-54931364-G-A is Benign according to our data. Variant chr16-54931364-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3530146.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX5	NM_005853.6 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 3	ENST00000394636.9	NP_005844.4	P78411-1
IRX5	NM_001252197.1 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 3		NP_001239126.1	P78411-2
IRX5	XM_011522809.1 link	c.-807G>A		upstream_gene_variant			XP_011521111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRX5	ENST00000394636.9 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 3	3	NM_005853.6	ENSP00000378132.4	P78411-1
IRX5	ENST00000320990.9 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 3	1		ENSP00000316250.5	P78411-2
IRX5	ENST00000560154.5 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 1 of 3	5		ENSP00000453660.1	H0YML8

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152166

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:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000287

AC:

AN:

237332

Hom.:

AF XY:

0.000344

AC XY:

AN XY:

130708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000566

Gnomad SAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000110

AC:

160

AN:

1454042

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

723672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74466

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:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000299

AC:

Asia WGS

AF:

0.00174

AC:

AN:

3466

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Aug 01, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

L;.;.;L

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.8

N;D;.;N

REVEL

Benign

0.082

Sift

Benign

0.036

D;D;.;D

Sift4G

Uncertain

0.026

D;T;D;D

Polyphen

0.87

P;.;P;.

Vest4

0.58

MutPred

0.24

Gain of glycosylation at A56 (P = 0.004);Gain of glycosylation at A56 (P = 0.004);Gain of glycosylation at A56 (P = 0.004);Gain of glycosylation at A56 (P = 0.004);

MVP

0.55

ClinPred

0.11

GERP RS

3.6

Varity_R

0.15

gMVP

0.62

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