Variant 8-90645778-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001008495.4(TMEM64):c.128C>A(p.Ala43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,020,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

TMEM64
NM_001008495.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0680

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:43643): (long intergenic non-protein coding RNA 534)

LINC00534 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.050176114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM64	NM_001008495.4 linkuse as main transcript	c.128C>A	p.Ala43Glu	missense_variant	1/3	ENST00000458549.7	NP_001008495.2
TMEM64	NM_001146273.1 linkuse as main transcript	c.128C>A	p.Ala43Glu	missense_variant	1/2		NP_001139745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM64	ENST00000458549.7 linkuse as main transcript	c.128C>A	p.Ala43Glu	missense_variant	1/3	1	NM_001008495.4	ENSP00000414786	P1	Q6YI46-1
LINC00534	ENST00000667296.1 linkuse as main transcript	n.457-23262G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

147160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000454

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

873462

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

407244

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.000168

GnomAD4 genome

AF:

0.0000204

AC:

AN:

147160

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71600

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000454

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

May 30, 2023

The c.128C>A (p.A43E) 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 128, causing the alanine (A) at amino acid position 43 to be replaced by a glutamic acid (E). 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

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.22

DANN

Benign

0.83

DEOGEN2

Benign

0.0086

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.020

Sift

Benign

0.27

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0

.;B

Vest4

0.087

MutPred

0.092

Loss of methylation at R48 (P = 0.0535);Loss of methylation at R48 (P = 0.0535);

MVP

0.099

MPC

1.9

ClinPred

0.16

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.22

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