11-118533010-C-T

Variant summary

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

The NM_032780.4(TMEM25):​c.476C>T​(p.Pro159Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 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: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TMEM25
NM_032780.4 missense

Scores

9
5
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.22
Variant links:
Genes affected
TMEM25 (HGNC:25890): (transmembrane protein 25) Predicted to be involved in negative regulation of excitatory postsynaptic potential and regulation of protein stability. Predicted to be located in late endosome and lysosome. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.784

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM25NM_032780.4 linkc.476C>T p.Pro159Leu missense_variant 4/9 ENST00000313236.10 NP_116169.2 Q86YD3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM25ENST00000313236.10 linkc.476C>T p.Pro159Leu missense_variant 4/91 NM_032780.4 ENSP00000315635.5 Q86YD3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251318
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

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 GeneticsFeb 27, 2023The c.476C>T (p.P159L) alteration is located in exon 4 (coding exon 3) of the TMEM25 gene. This alteration results from a C to T substitution at nucleotide position 476, causing the proline (P) at amino acid position 159 to be replaced by a leucine (L). 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
0.77
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.32
.;.;.;.;.;.;T;T;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;D;D;D;.
M_CAP
Benign
0.048
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.1
L;L;L;L;.;.;.;L;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-8.3
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;D;D;D;D
Vest4
0.89
MVP
0.61
MPC
0.64
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.82
gMVP
0.82

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: rs140936953; hg19: chr11-118403725; COSMIC: COSV57096998; COSMIC: COSV57096998; API