3-33093130-C-G

Variant names:

• chr3-33093130-C-G
• rs1700841005
• NM_001039770.3:c.1066G>C

Variant summary

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

The NM_001039770.3(TMPPE):​c.1066G>C​(p.Glu356Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000014 (0 hom.)
• Consequence: TMPPE NM_001039770.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.999

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 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=0.0469625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.1066G>C	p.Glu356Gln	missense_variant	Exon 2 of 2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.75+3881G>C		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.1066G>C	p.Glu356Gln	missense_variant	Exon 2 of 2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10	c.75+3881G>C		intron_variant	Intron 1 of 15	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066G>C (p.E356Q) alteration is located in exon 2 (coding exon 1) of the TMPPE gene. This alteration results from a G to C substitution at nucleotide position 1066, causing the glutamic acid (E) at amino acid position 356 to be replaced by a glutamine (Q). 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	0.060
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.61	.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.20
Sift	Benign	0.46	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0030	.;B
Vest4		0.052
MutPred		0.35		.;Loss of glycosylation at K353 (P = 0.0587);
MVP		0.17
MPC		0.38
ClinPred		0.099	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.42

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: rs1700841005; hg19: chr3-33134622;