Variant chr16-54284745-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024336.3(IRX3):c.1136C>T(p.Ala379Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,455,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

IRX3
NM_024336.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

IRX3 (HGNC:14360): (iroquois homeobox 3) IRX3 is a member of the Iroquois homeobox gene family (see IRX1; MIM 606197) and plays a role in an early step of neural development (Bellefroid et al., 1998 [PubMed 9427753]). Members of this family appear to play multiple roles during pattern formation of vertebrate embryos (Lewis et al., 1999 [PubMed 10370142]).[supplied by OMIM, Aug 2009]

IRX3 links:

IRX3 (HGNC:):

IRX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019351304).

BS2

High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRX3	NM_024336.3 linkuse as main transcript	c.1136C>T	p.Ala379Val	missense_variant	2/4	ENST00000329734.4	NP_077312.2	P78415
IRX3	XM_005256139.4 linkuse as main transcript	c.1136C>T	p.Ala379Val	missense_variant	2/4		XP_005256196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IRX3	ENST00000329734.4 linkuse as main transcript	c.1136C>T	p.Ala379Val	missense_variant	2/4	1	NM_024336.3	ENSP00000331608.3	P78415
IRX3	ENST00000558054.1 linkuse as main transcript	c.73-433C>T		intron_variant		2		ENSP00000463991.1	J3QR11
IRX3	ENST00000558180.2 linkuse as main transcript	n.915C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000688

AC:

AN:

50850

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

29114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.00312

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000972

Gnomad NFE exome

AF:

0.000943

Gnomad OTH exome

AF:

0.00126

GnomAD4 exome

AF:

0.000518

AC:

675

AN:

1303000

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

320

AN XY:

640220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000244

Gnomad4 ASJ exome

AF:

0.00392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000151

Gnomad4 FIN exome

AF:

0.000825

Gnomad4 NFE exome

AF:

0.000506

Gnomad4 OTH exome

AF:

0.000573

GnomAD4 genome

AF:

0.000355

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000602

Hom.:

Bravo

AF:

0.000446

ExAC

AF:

0.000111

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 18, 2021

The c.1136C>T (p.A379V) alteration is located in exon 2 (coding exon 2) of the IRX3 gene. This alteration results from a C to T substitution at nucleotide position 1136, causing the alanine (A) at amino acid position 379 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

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.1

REVEL

Benign

0.10

Sift

Benign

0.38

Sift4G

Benign

0.34

Polyphen

0.98

Vest4

0.24

MutPred

0.27

Loss of helix (P = 0.1299);

MVP

0.44

ClinPred

0.047

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.097

gMVP

0.47

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