1-32894830-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033504.4(TMEM54):c.644C>T(p.Thr215Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,452,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TMEM54
NM_033504.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.549

Publications

0 publications found

Variant links:

Genes affected

TMEM54 (HGNC:24143): (transmembrane protein 54) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM54 links:

HPCA (HGNC:5144): (hippocalcin) The protein encoded by this gene is a member of neuron-specific calcium-binding proteins family found in the retina and brain. This protein is associated with the plasma membrane. It has similarities to proteins located in the photoreceptor cells that regulate photosignal transduction in a calcium-sensitive manner. This protein displays recoverin activity and a calcium-dependent inhibition of rhodopsin kinase. It is identical to the rat and mouse hippocalcin proteins and thought to play an important role in neurons of the central nervous system in a number of species. [provided by RefSeq, Jul 2008]

HPCA Gene-Disease associations (from GenCC):

torsion dystonia 2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

HPCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.078029335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM54	NM_033504.4 link	c.644C>T	p.Thr215Ile	missense_variant	Exon 6 of 6	ENST00000373463.8	NP_277039.1	Q969K7-1
HPCA	NM_002143.3 link	c.*968G>A		downstream_gene_variant		ENST00000373467.4	NP_002134.2	P84074

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM54	ENST00000373463.8 link	c.644C>T	p.Thr215Ile	missense_variant	Exon 6 of 6	1	NM_033504.4	ENSP00000362562.3		Q969K7-1
HPCA	ENST00000373467.4 link	c.*968G>A		downstream_gene_variant		1	NM_002143.3	ENSP00000362566.3		P84074

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251222

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1452538

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

722258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

1103750

Other (OTH)

AF:

0.0000167

AC:

AN:

60016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.644C>T (p.T215I) alteration is located in exon 6 (coding exon 6) of the TMEM54 gene. This alteration results from a C to T substitution at nucleotide position 644, causing the threonine (T) at amino acid position 215 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

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.078

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.55

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.070

T;T

Polyphen

0.43

B;P

Vest4

0.12

MutPred

0.14

Loss of disorder (P = 0.0145);.;

MVP

0.14

MPC

0.41

ClinPred

0.32

GERP RS

5.2

Varity_R

0.10

gMVP

0.17

Mutation Taster

=83/17

polymorphism

(source)

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

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1-32894830-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over