chr12-129074500-A-C

Position:

• chr12-129074500-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133448.3(TMEM132D):​c.2675T>G​(p.Val892Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM132D NM_133448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

Genes affected

TMEM132D (HGNC:29411): (transmembrane protein 132D)

LOC124903086 (HGNC:):

ACMG classification

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=0.033257335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM132D	NM_133448.3	c.2675T>G	p.Val892Gly	missense_variant	9/9	ENST00000422113.7	NP_597705.2
LOC124903086	XR_007063612.1	n.87-406A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM132D	ENST00000422113.7	c.2675T>G	p.Val892Gly	missense_variant	9/9	1	NM_133448.3	ENSP00000408581.2
TMEM132D	ENST00000389441.8	c.1289T>G	p.Val430Gly	missense_variant	4/4	1		ENSP00000374092.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.2675T>G (p.V892G) alteration is located in exon 9 (coding exon 9) of the TMEM132D gene. This alteration results from a T to G substitution at nucleotide position 2675, causing the valine (V) at amino acid position 892 to be replaced by a glycine (G). 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	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.2
DANN	Benign	0.94
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.077
Sift	Benign	0.56	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0010	B;B
Vest4		0.12
MutPred		0.27		.;Gain of catalytic residue at A890 (P = 0.0526);
MVP		0.043
MPC		0.31
ClinPred		0.086	T
GERP RS		-1.9
Varity_R		0.24
gMVP		0.53

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

Other links and lift over

dbSNP: rs138024935; hg19: chr12-129559045;