Variant 5-2748872-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_033267.5(IRX2):c.836C>T(p.Pro279Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000181 in 1,593,036 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P279S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

IRX2
NM_033267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

IRX2 (HGNC:14359): (iroquois homeobox 2) IRX2 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[supplied by OMIM, Apr 2004]

IRX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21902981).

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IRX2	NM_033267.5 linkuse as main transcript	c.836C>T	p.Pro279Leu	missense_variant	3/4	ENST00000302057.6
IRX2	NM_001134222.2 linkuse as main transcript	c.836C>T	p.Pro279Leu	missense_variant	3/5
IRX2	XM_011513979.3 linkuse as main transcript	c.836C>T	p.Pro279Leu	missense_variant	3/5
IRX2	XM_024454379.2 linkuse as main transcript	c.557C>T	p.Pro186Leu	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX2	ENST00000302057.6 linkuse as main transcript	c.836C>T	p.Pro279Leu	missense_variant	3/4	1	NM_033267.5	P1
IRX2	ENST00000382611.10 linkuse as main transcript	c.836C>T	p.Pro279Leu	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000177

AC:

AN:

214710

Hom.:

AF XY:

0.000175

AC XY:

AN XY:

119916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000509

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:

0.000175

Gnomad OTH exome

AF:

0.000731

GnomAD4 exome

AF:

0.000171

AC:

247

AN:

1440816

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

125

AN XY:

717032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000541

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:

0.000168

Gnomad4 OTH exome

AF:

0.000467

GnomAD4 genome

AF:

0.000276

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000314

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000153

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.836C>T (p.P279L) alteration is located in exon 3 (coding exon 3) of the IRX2 gene. This alteration results from a C to T substitution at nucleotide position 836, causing the proline (P) at amino acid position 279 to be replaced by a leucine (L). 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

0.068

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.74

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.15

Sift

Benign

0.061

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.99

D;D

Vest4

0.23

MVP

0.61

MPC

0.44

ClinPred

0.11

GERP RS

3.6

Varity_R

0.19

gMVP

0.25

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