Genetic Variant TMEM132C:p.Gly34Arg (chr12-128414746-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001136103.3(TMEM132C):c.100G>A(p.Gly34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,525,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TMEM132C
NM_001136103.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

Variant links:

Genes affected

TMEM132C (HGNC:25436): (transmembrane protein 132C) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM132C links:

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=0.05054754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM132C	NM_001136103.3 link	c.100G>A	p.Gly34Arg	missense_variant	Exon 2 of 9	ENST00000435159.3	NP_001129575.2	Q8N3T6
TMEM132C	NM_001387058.1 link	c.40G>A	p.Gly14Arg	missense_variant	Exon 2 of 9		NP_001373987.1
TMEM132C	XM_047429886.1 link	c.100G>A	p.Gly34Arg	missense_variant	Exon 2 of 9		XP_047285842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM132C	ENST00000435159.3 link	c.100G>A	p.Gly34Arg	missense_variant	Exon 2 of 9	5	NM_001136103.3	ENSP00000410852.2		Q8N3T6

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000166

AC:

AN:

138428

Hom.:

AF XY:

0.000190

AC XY:

AN XY:

73878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00171

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000351

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

173

AN:

1373840

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

675704

show subpopulations

Gnomad4 AFR exome

AF:

0.000512

Gnomad4 AMR exome

AF:

0.000172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00141

Gnomad4 SAS exome

AF:

0.0000513

Gnomad4 FIN exome

AF:

0.0000281

Gnomad4 NFE exome

AF:

0.0000794

Gnomad4 OTH exome

AF:

0.000192

GnomAD4 genome

AF:

0.000243

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000314

Asia WGS

AF:

0.000577

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

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100G>A (p.G34R) alteration is located in exon 2 (coding exon 2) of the TMEM132C gene. This alteration results from a G to A substitution at nucleotide position 100, causing the glycine (G) at amino acid position 34 to be replaced by an arginine (R). 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

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

Eigen

Benign

0.030

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.62

M_CAP

Benign

0.0098

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.021

Vest4

0.18

MutPred

0.52

Gain of solvent accessibility (P = 0.0055);

MVP

0.043

MPC

0.39

ClinPred

0.29

GERP RS

4.3

Varity_R

0.17

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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