1-46673022-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The ENST00000415500.1(TEX38):​c.-40-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,551,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

TEX38
ENST00000415500.1 splice_acceptor

Scores

1
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21
Variant links:
Genes affected
TEX38 (HGNC:29589): (testis expressed 38) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
ATPAF1 (HGNC:18803): (ATP synthase mitochondrial F1 complex assembly factor 1) This gene encodes an assembly factor for the F(1) component of the mitochondrial ATP synthase. This protein binds specifically to the F1 beta subunit and is thought to prevent this subunit from forming nonproductive homooligomers during enzyme assembly. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.1501272 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TEX38NM_001145474.4 linkuse as main transcriptc.187A>T p.Ser63Cys missense_variant 2/2 ENST00000334122.5
TEX38NM_001300864.2 linkuse as main transcriptc.-40-2A>T splice_acceptor_variant
TEX38NM_001300863.2 linkuse as main transcriptc.25A>T p.Ser9Cys missense_variant 2/2
TEX38XM_011541421.4 linkuse as main transcriptc.190A>T p.Ser64Cys missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TEX38ENST00000334122.5 linkuse as main transcriptc.187A>T p.Ser63Cys missense_variant 2/21 NM_001145474.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000243
AC:
38
AN:
156154
Hom.:
0
AF XY:
0.000290
AC XY:
24
AN XY:
82764
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:
0.00167
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000879
AC:
123
AN:
1399400
Hom.:
0
Cov.:
31
AF XY:
0.000112
AC XY:
77
AN XY:
690212
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:
0.00133
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000278
Gnomad4 OTH exome
AF:
0.000259
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152304
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000225
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.000270
AC:
7
Asia WGS
AF:
0.00289
AC:
10
AN:
3478

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 GeneticsSep 25, 2023The c.187A>T (p.S63C) alteration is located in exon 2 (coding exon 2) of the TEX38 gene. This alteration results from a A to T substitution at nucleotide position 187, causing the serine (S) at amino acid position 63 to be replaced by a cysteine (C). 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
0.42
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
28
DANN
Uncertain
0.98
DEOGEN2
Benign
0.069
T;T;T
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.065
T;T;T
MutationAssessor
Benign
1.7
.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-4.0
D;D;D
Sift
Uncertain
0.0050
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.47
MVP
0.84
GERP RS
5.5
Varity_R
0.23
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs563308319; hg19: chr1-47138694; API