rs770577561

Variant names:

• chr12-129081953-C-A
• rs770577561
• NM_133448.3:c.1729G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-129081953-C-A
• chr12-129081953-C-G
• chr12-129081953-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133448.3(TMEM132D):​c.1729G>T​(p.Val577Leu) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM132D NM_133448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95
• Publications: 0 publications found

Genes affected

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

TMEM132D Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC124903086 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29633582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM132D	NM_133448.3	c.1729G>T	p.Val577Leu	missense_variant	Exon 7 of 9	ENST00000422113.7	NP_597705.2
LOC124903086	XR_007063612.1	n.257-496C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM132D	ENST00000422113.7	c.1729G>T	p.Val577Leu	missense_variant	Exon 7 of 9	1	NM_133448.3	ENSP00000408581.2
TMEM132D	ENST00000389441.8	c.343G>T	p.Val115Leu	missense_variant	Exon 2 of 4	1		ENSP00000374092.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.048	.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L
PhyloP100		3.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.065
Sift	Benign	0.32	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0070	B;B
Vest4		0.59
MutPred		0.44		.;Gain of catalytic residue at M576 (P = 0.0186);
MVP		0.043
MPC		0.45
ClinPred		0.61	D
GERP RS		3.8
Varity_R		0.11
gMVP		0.56
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs770577561; hg19: chr12-129566498; COSMIC: COSV101243107;