7-112775315-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022484.6(TMEM168):ā€‹c.1132A>Gā€‹(p.Thr378Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,612,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T378K) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 31)
Exomes š‘“: 0.000062 ( 0 hom. )

Consequence

TMEM168
NM_022484.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0170
Variant links:
Genes affected
TMEM168 (HGNC:25826): (transmembrane protein 168) Located in transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]
LINC03076 (HGNC:56656): (long intergenic non-protein coding RNA 3076)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TMEM168NM_022484.6 linkuse as main transcriptc.1132A>G p.Thr378Ala missense_variant 3/5 ENST00000312814.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TMEM168ENST00000312814.11 linkuse as main transcriptc.1132A>G p.Thr378Ala missense_variant 3/51 NM_022484.6 P1Q9H0V1-1
LINC03076ENST00000656697.1 linkuse as main transcriptn.469-121038T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152198
Hom.:
0
Cov.:
31
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249544
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134930
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1460086
Hom.:
0
Cov.:
31
AF XY:
0.0000441
AC XY:
32
AN XY:
726290
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:
0.00
Gnomad4 FIN exome
AF:
0.0000750
Gnomad4 NFE exome
AF:
0.0000756
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152198
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
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 28, 2023The c.1132A>G (p.T378A) alteration is located in exon 3 (coding exon 2) of the TMEM168 gene. This alteration results from a A to G substitution at nucleotide position 1132, causing the threonine (T) at amino acid position 378 to be replaced by an alanine (A). 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
0.063
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Benign
0.024
T;T;T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.65
.;T;T;T
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.070
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.76
N;N;.;.
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.68
N;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.71
T;T;D;T
Sift4G
Benign
0.20
T;T;T;.
Polyphen
0.0
B;B;.;.
Vest4
0.19
MVP
0.19
MPC
0.10
ClinPred
0.11
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.028
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.26
Position offset: -1

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: rs148063778; hg19: chr7-112415370; API