chr12-111936703-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001193531.2(TMEM116):​c.577C>T​(p.Leu193Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM116
NM_001193531.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.160

Publications

0 publications found
Variant links:
Genes affected
TMEM116 (HGNC:25084): (transmembrane protein 116) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09896022).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM116NM_001193531.2 linkc.577C>T p.Leu193Phe missense_variant Exon 8 of 11 ENST00000552374.7 NP_001180460.1 Q8NCL8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM116ENST00000552374.7 linkc.577C>T p.Leu193Phe missense_variant Exon 8 of 11 1 NM_001193531.2 ENSP00000447731.1 Q8NCL8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461716
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727150
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111926
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.577C>T (p.L193F) alteration is located in exon 8 (coding exon 7) of the TMEM116 gene. This alteration results from a C to T substitution at nucleotide position 577, causing the leucine (L) at amino acid position 193 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
Benign
0.087
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.037
T;.;.;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.70
T;T;T;T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.099
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.61
N;.;.;.
PhyloP100
0.16
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.8
N;N;N;.
REVEL
Benign
0.013
Sift
Benign
0.15
T;T;T;.
Sift4G
Benign
0.21
T;T;T;T
Polyphen
0.026
B;.;.;.
Vest4
0.15
MutPred
0.35
Gain of catalytic residue at S99 (P = 0.0014);.;.;Gain of catalytic residue at S99 (P = 0.0014);
MVP
0.13
MPC
0.16
ClinPred
0.085
T
GERP RS
0.58
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.38
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1314366033; hg19: chr12-112374507; API