Variant 22-35084444-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_001303508.2(ISX):c.443C>T(p.Ala148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ISX
NM_001303508.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.190

Variant links:

Genes affected

ISX (HGNC:28084): (intestine specific homeobox) Homeobox genes encode DNA-binding proteins, many of which are thought to be involved in early embryonic development. Homeobox genes encode a DNA-binding domain of 60 to 63 amino acids referred to as the homeodomain. This gene is a member of the RAXLX homeobox gene family. [provided by RefSeq, Jul 2008]

ISX 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=0.042761832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISX	NM_001303508.2 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	4/5	ENST00000404699.7
ISX	XM_047441598.1 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISX	ENST00000404699.7 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	4/5	1	NM_001303508.2	P1
ISX	ENST00000308700.6 linkuse as main transcript	c.443C>T	p.Ala148Val	missense_variant	3/4	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250664

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135480

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000491

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000824

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

Aug 22, 2023

The c.443C>T (p.A148V) alteration is located in exon 3 (coding exon 3) of the ISX gene. This alteration results from a C to T substitution at nucleotide position 443, causing the alanine (A) at amino acid position 148 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

0.076

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.2

DANN

Benign

0.94

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.45

.;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.19

Sift

Uncertain

0.012

D;D

Sift4G

Benign

0.077

T;T

Polyphen

0.12

B;B

Vest4

0.047

MutPred

0.31

Loss of disorder (P = 0.0655);Loss of disorder (P = 0.0655);

MVP

0.67

MPC

0.011

ClinPred

0.026

GERP RS

-1.7

Varity_R

0.060

gMVP

0.31

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