Variant 8-90631619-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001008495.4(TMEM64):c.884C>T(p.Thr295Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM64
NM_001008495.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.84

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM64	NM_001008495.4 linkuse as main transcript	c.884C>T	p.Thr295Ile	missense_variant	2/3	ENST00000458549.7	NP_001008495.2
TMEM64	NM_001146273.1 linkuse as main transcript	c.796-5757C>T		intron_variant			NP_001139745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM64	ENST00000458549.7 linkuse as main transcript	c.884C>T	p.Thr295Ile	missense_variant	2/3	1	NM_001008495.4	ENSP00000414786	P1	Q6YI46-1
LINC00534	ENST00000667296.1 linkuse as main transcript	n.457-37421G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727054

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

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

Jan 26, 2022

The c.884C>T (p.T295I) alteration is located in exon 2 (coding exon 2) of the TMEM64 gene. This alteration results from a C to T substitution at nucleotide position 884, causing the threonine (T) at amino acid position 295 to be replaced by an isoleucine (I). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0091

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.0070

D;D;.

Polyphen

0.99

D;P;.

Vest4

0.95

MutPred

0.56

Loss of glycosylation at T295 (P = 0.1317);.;.;

MVP

0.37

MPC

0.59

ClinPred

0.99

GERP RS

5.8

Varity_R

0.54

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over