Variant 3-133380229-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_023943.4(TMEM108):c.518G>A(p.Arg173Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,010 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

TMEM108
NM_023943.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

Variant links:

Genes affected

TMEM108 (HGNC:28451): (transmembrane protein 108) Predicted to be involved in several processes, including cellular response to brain-derived neurotrophic factor stimulus; nervous system development; and regulation of signal transduction. Predicted to be located in somatodendritic compartment. Predicted to be active in axon; endosome; and postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

TMEM108 links:

LOC101927432 (HGNC:):

LOC101927432 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039824307).

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM108	NM_023943.4 linkuse as main transcript	c.518G>A	p.Arg173Gln	missense_variant	4/6	ENST00000321871.11	NP_076432.1
LOC101927432	XR_007096099.1 linkuse as main transcript	n.5957+1434C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM108	ENST00000321871.11 linkuse as main transcript	c.518G>A	p.Arg173Gln	missense_variant	4/6	1	NM_023943.4	ENSP00000324651	P1	Q6UXF1-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151848

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000427

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

246638

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

134074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000460

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000333

AC:

486

AN:

1461044

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

726770

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000403

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000191

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74272

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000427

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.518G>A (p.R173Q) alteration is located in exon 4 (coding exon 2) of the TMEM108 gene. This alteration results from a G to A substitution at nucleotide position 518, causing the arginine (R) at amino acid position 173 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

T;T;.

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.057

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.037

Sift

Benign

0.091

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

1.0

D;D;B

Vest4

0.35

MVP

0.11

MPC

0.80

ClinPred

0.036

GERP RS

2.9

Varity_R

0.059

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over