Genetic Variant IRX6:p.Pro95Ser (chr16-55326573-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_024335.3(IRX6):c.283C>T(p.Pro95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,562,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

IRX6
NM_024335.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0280

Variant links:

Genes affected

IRX6 (HGNC:14675): (iroquois homeobox 6) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of transcription, DNA-templated. Predicted to act upstream of or within detection of visible light; negative regulation of transcription, DNA-templated; and retina morphogenesis in camera-type eye. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRX6 links:

ENSG00000259283 (HGNC:):

ENSG00000259283 links:

Genome browser will be placed here

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=0.014696211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX6	NM_024335.3 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 2 of 6	ENST00000290552.8	NP_077311.2	P78412
IRX6	XM_005256137.4 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 2 of 6		XP_005256194.1	P78412

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRX6	ENST00000290552.8 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 2 of 6	1	NM_024335.3	ENSP00000290552.8	P78412
IRX6	ENST00000558315.1 link	n.449C>T		non_coding_transcript_exon_variant	Exon 2 of 5	1
ENSG00000259283	ENST00000558730.2 link	n.88+6928G>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

169660

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

90712

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:

0.000385

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.000418

AC:

589

AN:

1410472

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

284

AN XY:

696340

show subpopulations

Gnomad4 AFR exome

AF:

0.0000619

Gnomad4 AMR exome

AF:

0.0000526

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.000488

Gnomad4 OTH exome

AF:

0.000942

GnomAD4 genome

AF:

0.000250

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000469

AC:

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283C>T (p.P95S) alteration is located in exon 2 (coding exon 2) of the IRX6 gene. This alteration results from a C to T substitution at nucleotide position 283, causing the proline (P) at amino acid position 95 to be replaced by a serine (S). 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

0.058

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.1

DANN

Benign

0.66

DEOGEN2

Benign

0.0090

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.62

M_CAP

Benign

0.023

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.31

PROVEAN

Benign

2.3

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.19

MVP

0.75

MPC

0.092

ClinPred

0.038

GERP RS

2.9

Varity_R

0.040

gMVP

0.37

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