chr3-33093243-C-A

Variant names:

• chr3-33093243-C-A
• NM_001039770.3:c.953G>T

Variant summary

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

The NM_001039770.3(TMPPE):​c.953G>T​(p.Gly318Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.558

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116740495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.953G>T	p.Gly318Val	missense_variant	Exon 2 of 2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.75+3768G>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.953G>T	p.Gly318Val	missense_variant	Exon 2 of 2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10	c.75+3768G>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: 1461606 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727094

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.953G>T (p.G318V) 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 953, causing the glycine (G) at amino acid position 318 to be replaced by a valine (V). 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	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.4
DANN	Benign	0.67
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.26	N;N
REVEL	Benign	0.13
Sift	Benign	0.068	T;D
Sift4G	Uncertain	0.032	D;T
Polyphen		1.0	.;D
Vest4		0.25
MutPred		0.34		.;Gain of glycosylation at S323 (P = 0.0303);
MVP		0.13
MPC		1.1
ClinPred		0.27	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.37

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: chr3-33134735;