22-35082643-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001303508.2(ISX):​c.355A>T​(p.Ile119Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ISX
NM_001303508.2 missense

Scores

6
12
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ISXNM_001303508.2 linkuse as main transcriptc.355A>T p.Ile119Phe missense_variant 3/5 ENST00000404699.7
ISXXM_047441598.1 linkuse as main transcriptc.355A>T p.Ile119Phe missense_variant 2/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ISXENST00000404699.7 linkuse as main transcriptc.355A>T p.Ile119Phe missense_variant 3/51 NM_001303508.2 P1
ISXENST00000308700.6 linkuse as main transcriptc.355A>T p.Ile119Phe missense_variant 2/41 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152186
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251240
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135810
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461844
Hom.:
0
Cov.:
36
AF XY:
0.0000110
AC XY:
8
AN XY:
727222
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152186
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsApr 04, 2023The c.355A>T (p.I119F) alteration is located in exon 2 (coding exon 2) of the ISX gene. This alteration results from a A to T substitution at nucleotide position 355, causing the isoleucine (I) at amino acid position 119 to be replaced by a phenylalanine (F). 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
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;D
Vest4
0.70
MutPred
0.43
Gain of methylation at R118 (P = 0.0437);Gain of methylation at R118 (P = 0.0437);
MVP
0.95
MPC
0.065
ClinPred
0.98
D
GERP RS
4.9
Varity_R
0.59
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs751393633; hg19: chr22-35478636; API