chr1-32894824-GAGCTGGTGCAGCTC-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_033504.4(TMEM54):c.636_649delGAGCTGCACCAGCT(p.Ser213fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,611,776 control chromosomes in the GnomAD database, including 15 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 13 hom. )

Consequence

TMEM54
NM_033504.4 frameshift

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.823

Publications

3 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 -6 ACMG points.

BP6

Variant 1-32894824-GAGCTGGTGCAGCTC-G is Benign according to our data. Variant chr1-32894824-GAGCTGGTGCAGCTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 2691376.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM54	NM_033504.4 link	c.636_649delGAGCTGCACCAGCT	p.Ser213fs	frameshift_variant	Exon 6 of 6	ENST00000373463.8	NP_277039.1	Q969K7-1
HPCA	NM_002143.3 link	c.963_976delAGCTGGTGCAGCTC		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.636_649delGAGCTGCACCAGCT	p.Ser213fs	frameshift_variant	Exon 6 of 6	1	NM_033504.4	ENSP00000362562.3		Q969K7-1
HPCA	ENST00000373467.4 link	c.963_976delAGCTGGTGCAGCTC		downstream_gene_variant		1	NM_002143.3	ENSP00000362566.3		P84074

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00166

AC:

418

AN:

251234

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00251

AC:

3663

AN:

1459492

Hom.:

AF XY:

0.00246

AC XY:

1786

AN XY:

725552

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000359

AC:

AN:

33438

American (AMR)

AF:

0.00244

AC:

109

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00300

AC:

3328

AN:

1110086

Other (OTH)

AF:

0.00231

AC:

139

AN:

60266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152284

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41556

American (AMR)

AF:

0.00216

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00257

AC:

175

AN:

68014

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00175

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM54 c.636_649del14 (p.Ser213X) results in a premature termination codon and is predicted to cause a truncation of the encoded protein but is not expected to cause absence of the protein due to nonsense mediated decay. Furthermore, the molecular mechanism of disease attributed to TMEM54 is currently unknown. The variant allele was found at a frequency of 0.0024 in 1611776 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 15 homozygotes, suggesting the variant is likely a benign polymorphism. To our knowledge, no occurrence of c.636_649del14 in individuals affected with TMEM54-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.82

Mutation Taster

=99/101

disease causing (long InDel)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr1-32894824-GAGCTGGTGCAGCTC-G

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