Variant chr5-3596197-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024337.4(IRX1):c.92C>T(p.Ala31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,037,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

IRX1
NM_024337.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

Variant links:

Genes affected

IRX1 (HGNC:14358): (iroquois homeobox 1) This gene encodes a member of the Iroquois homeobox protein family. Homeobox genes in this family are involved in pattern formation in the embryo. The gene product has been identified as a tumor suppressor in gastric (PMID: 21602894, 20440264) and head and neck cancers (PMID: 18559491). A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Dec 2011]

IRX1 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0064484775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX1	NM_024337.4 linkuse as main transcript	c.92C>T	p.Ala31Val	missense_variant	1/4	ENST00000302006.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX1	ENST00000302006.4 linkuse as main transcript	c.92C>T	p.Ala31Val	missense_variant	1/4	1	NM_024337.4	P1
	ENST00000559410.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000259

AC:

AN:

146976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000540

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00375

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000166

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0120

AC:

AN:

250

Hom.:

AF XY:

0.00714

AC XY:

AN XY:

140

show subpopulations

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00971

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.000172

AC:

153

AN:

890432

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

415352

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:

0.00208

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000109

Gnomad4 OTH exome

AF:

0.000683

GnomAD4 genome

AF:

0.000258

AC:

AN:

147072

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

AN XY:

71612

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000540

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00375

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000166

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000181

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

Aug 12, 2021

The c.92C>T (p.A31V) alteration is located in exon 1 (coding exon 1) of the IRX1 gene. This alteration results from a C to T substitution at nucleotide position 92, causing the alanine (A) at amino acid position 31 to be replaced by a valine (V). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.95

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.1

REVEL

Benign

0.14

Sift

Benign

0.16

Sift4G

Benign

0.087

Polyphen

0.96

Vest4

0.25

MutPred

0.40

Loss of loop (P = 0.0374);

ClinPred

0.20

GERP RS

2.4

Varity_R

0.12

gMVP

0.48

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