3-33093568-C-A

Variant names:

• chr3-33093568-C-A
• NM_001039770.3:c.628G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001039770.3(TMPPE):​c.628G>T​(p.Val210Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMPPE NM_001039770.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

Genes affected

TMPPE (HGNC:33865): (transmembrane protein with metallophosphoesterase domain) Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30451617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.628G>T	p.Val210Leu	missense_variant	Exon 2 of 2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.75+3443G>T		intron_variant	Intron 1 of 15	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPPE	ENST00000342462.5	c.628G>T	p.Val210Leu	missense_variant	Exon 2 of 2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10	c.75+3443G>T		intron_variant	Intron 1 of 15	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628G>T (p.V210L) alteration is located in exon 2 (coding exon 1) of the TMPPE gene. This alteration results from a G to T substitution at nucleotide position 628, causing the valine (V) at amino acid position 210 to be replaced by a leucine (L). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.052	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.63	.;P
Vest4		0.39
MutPred		0.58		.;Loss of catalytic residue at V210 (P = 0.0989);
MVP		0.22
MPC		0.43
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.098
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33135060;