chr1-43272769-C-T

Variant summary

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

The NM_144626.3(TMEM125):​c.47C>T​(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,525,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P16R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMEM125
NM_144626.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.453
Variant links:
Genes affected
TMEM125 (HGNC:28275): (transmembrane protein 125) Predicted to be integral component of 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=0.046636313).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM125NM_144626.3 linkc.47C>T p.Pro16Leu missense_variant Exon 4 of 4 ENST00000439858.6 NP_653227.1 Q96AQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM125ENST00000439858.6 linkc.47C>T p.Pro16Leu missense_variant Exon 4 of 4 2 NM_144626.3 ENSP00000429775.1 Q96AQ2
TMEM125ENST00000432792.6 linkc.47C>T p.Pro16Leu missense_variant Exon 4 of 4 1 ENSP00000429275.1 Q96AQ2
TMEM125ENST00000456751.1 linkc.47C>T p.???16??? splice_region_variant, synonymous_variant Exon 3 of 3 3 ENSP00000428627.1 E5RHB0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
2
AN:
167724
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
90042
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000676
Gnomad SAS exome
AF:
0.0000609
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000160
AC:
22
AN:
1373396
Hom.:
0
Cov.:
31
AF XY:
0.0000149
AC XY:
10
AN XY:
673186
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:
0.000110
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000122
Gnomad4 OTH exome
AF:
0.0000177
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 03, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.47C>T (p.P16L) alteration is located in exon 4 (coding exon 1) of the TMEM125 gene. This alteration results from a C to T substitution at nucleotide position 47, causing the proline (P) at amino acid position 16 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
Benign
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
14
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0048
T;T
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.65
.;T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.047
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.33
N;N
REVEL
Benign
0.010
Sift
Benign
0.26
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.0060
B;B
Vest4
0.15
MutPred
0.24
Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);
MVP
0.48
MPC
0.13
ClinPred
0.11
T
GERP RS
1.6
Varity_R
0.042
gMVP
0.42

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: rs1471313634; hg19: chr1-43738440; API