17-7355850-C-T

Variant summary

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

The NM_001320436.2(TMEM95):​c.239C>T​(p.Ala80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TMEM95
NM_001320436.2 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.581
Variant links:
Genes affected
TMEM95 (HGNC:27898): (transmembrane protein 95) Predicted to be involved in fusion of sperm to egg plasma membrane involved in single fertilization. Predicted to be located in sperm plasma membrane. Predicted to be integral component of membrane. Predicted to be active in acrosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.037657768).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM95NM_001320436.2 linkc.239C>T p.Ala80Val missense_variant Exon 3 of 7 ENST00000576060.6 NP_001307365.1 Q3KNT9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM95ENST00000576060.6 linkc.239C>T p.Ala80Val missense_variant Exon 3 of 7 1 NM_001320436.2 ENSP00000460828.1 Q3KNT9-1
TMEM95ENST00000389982.8 linkc.239C>T p.Ala80Val missense_variant Exon 3 of 7 1 ENSP00000374632.4 Q3KNT9-3
TMEM95ENST00000330767.4 linkc.239C>T p.Ala80Val missense_variant Exon 3 of 7 1 ENSP00000331466.4 Q3KNT9-2

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152026
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000183
AC:
46
AN:
251388
Hom.:
0
AF XY:
0.000169
AC XY:
23
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000463
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:
0.000246
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000127
AC:
186
AN:
1461846
Hom.:
0
Cov.:
34
AF XY:
0.000122
AC XY:
89
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000447
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:
0.000147
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152026
Hom.:
0
Cov.:
31
AF XY:
0.0000808
AC XY:
6
AN XY:
74236
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000208
Hom.:
1
Bravo
AF:
0.000140
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 02, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.239C>T (p.A80V) alteration is located in exon 3 (coding exon 3) of the TMEM95 gene. This alteration results from a C to T substitution at nucleotide position 239, causing the alanine (A) at amino acid position 80 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
0.13
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
.;T;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.64
FATHMM_MKL
Benign
0.071
N
LIST_S2
Benign
0.60
T;T;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.038
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Uncertain
-2.8
D;.;D
REVEL
Benign
0.025
Sift
Uncertain
0.012
D;.;D
Sift4G
Uncertain
0.017
D;D;D
Polyphen
0.25
B;B;B
Vest4
0.28
MVP
0.13
MPC
0.14
ClinPred
0.065
T
GERP RS
3.5
Varity_R
0.025
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs139214770; hg19: chr17-7259169; COSMIC: COSV50134077; COSMIC: COSV50134077; API