Variant 8-90645665-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001008495.4(TMEM64):c.241C>A(p.Leu81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,369,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMEM64
NM_001008495.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

TMEM64 (HGNC:25441): (transmembrane protein 64) Predicted to be involved in negative regulation of canonical Wnt signaling pathway; negative regulation of osteoblast differentiation; and positive regulation of fat cell differentiation. Predicted to act upstream of or within several processes, including positive regulation of bone resorption; positive regulation of osteoclast differentiation; and regulation of ATPase activity. Predicted to be located in endoplasmic reticulum. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM64 links:

LINC00534 (HGNC:):

LINC00534 links:

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ACMG classification

Classification made for transcript

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=0.1444895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM64	NM_001008495.4 linkuse as main transcript	c.241C>A	p.Leu81Met	missense_variant	1/3	ENST00000458549.7	NP_001008495.2	Q6YI46-1
TMEM64	NM_001146273.1 linkuse as main transcript	c.241C>A	p.Leu81Met	missense_variant	1/2		NP_001139745.1	Q6YI46-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM64	ENST00000458549.7 linkuse as main transcript	c.241C>A	p.Leu81Met	missense_variant	1/3	1	NM_001008495.4	ENSP00000414786.2		Q6YI46-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000593

AC:

AN:

117954

Hom.:

AF XY:

0.0000772

AC XY:

AN XY:

64808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000342

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1369218

Hom.:

Cov.:

AF XY:

0.0000163

AC XY:

AN XY:

675116

show subpopulations

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:

0.000194

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000701

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

The c.241C>A (p.L81M) alteration is located in exon 1 (coding exon 1) of the TMEM64 gene. This alteration results from a C to A substitution at nucleotide position 241, causing the leucine (L) at amino acid position 81 to be replaced by a methionine (M). 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

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.020

.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.44

T;T

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.053

Sift

Benign

0.060

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.39

.;B

Vest4

0.22

MutPred

0.096

Gain of glycosylation at P84 (P = 0.2531);Gain of glycosylation at P84 (P = 0.2531);

MVP

0.014

MPC

2.1

ClinPred

0.19

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over