NM_033504.4:c.338T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033504.4(TMEM54):c.338T>C(p.Leu113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,562,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

TMEM54
NM_033504.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2277256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM54	NM_033504.4 link	c.338T>C	p.Leu113Ser	missense_variant	Exon 4 of 6	ENST00000373463.8	NP_277039.1	Q969K7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM54	ENST00000373463.8 link	c.338T>C	p.Leu113Ser	missense_variant	Exon 4 of 6	1	NM_033504.4	ENSP00000362562.3		Q969K7-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000353

AC:

AN:

170084

AF XY:

0.0000334

show subpopulations

Gnomad AFR exome

AF:

0.000595

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000993

AC:

AN:

1409880

Hom.:

Cov.:

AF XY:

0.00000718

AC XY:

AN XY:

696274

show subpopulations

African (AFR)

AF:

0.000432

AC:

AN:

32408

American (AMR)

AF:

0.00

AC:

AN:

36420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25232

East Asian (EAS)

AF:

0.00

AC:

AN:

37042

South Asian (SAS)

AF:

0.00

AC:

AN:

80000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084792

Other (OTH)

AF:

0.00

AC:

AN:

58484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000687

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000341

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.338T>C (p.L113S) alteration is located in exon 4 (coding exon 4) of the TMEM54 gene. This alteration results from a T to C substitution at nucleotide position 338, causing the leucine (L) at amino acid position 113 to be replaced by a serine (S). 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

0.22

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.56

M_CAP

Benign

0.053

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.80

MutationAssessor

Benign

2.0

PhyloP100

2.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.21

Sift

Uncertain

0.0040

Sift4G

Benign

0.38

Polyphen

1.0

Vest4

0.37

MVP

0.45

MPC

0.99

ClinPred

0.32

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.60

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_033504.4:c.338T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over