12-125349983-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366854.1(TMEM132B):c.599G>A(p.Ser200Asn) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM132B NM_001366854.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

TMEM132B (HGNC:29397): (transmembrane protein 132B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11483756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM132B	NM_001366854.1	c.599G>A	p.Ser200Asn	missense_variant	2/9	ENST00000682704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM132B	ENST00000682704.1	c.599G>A	p.Ser200Asn	missense_variant	2/9		NM_001366854.1	P2
TMEM132B	ENST00000299308.7	c.584G>A	p.Ser195Asn	missense_variant	2/9	5		A2
TMEM132B	ENST00000534945.2	n.532G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 12, 2022

The c.584G>A (p.S195N) alteration is located in exon 2 (coding exon 2) of the TMEM132B gene. This alteration results from a G to A substitution at nucleotide position 584, causing the serine (S) at amino acid position 195 to be replaced by an asparagine (N). 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	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.10
Sift	Benign	0.31	T
Sift4G	Benign	0.85	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.48		Gain of catalytic residue at S195 (P = 0.0088);
MVP		0.29
MPC		0.24
ClinPred		0.31	T
GERP RS		3.1
Varity_R		0.050
gMVP		0.59

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: rs917663571; hg19: chr12-125834529;