rs1641578774

Variant names:

• chr1-32895734-C-G
• rs1641578774
• NM_033504.4:c.280G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033504.4(TMEM54):​c.280G>C​(p.Val94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TMEM54 NM_033504.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81
• Publications: 0 publications found

Genes affected

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

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)

ACMG classification

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=0.17716306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM54	NM_033504.4	c.280G>C	p.Val94Leu	missense_variant	Exon 4 of 6	ENST00000373463.8	NP_277039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM54	ENST00000373463.8	c.280G>C	p.Val94Leu	missense_variant	Exon 4 of 6	1	NM_033504.4	ENSP00000362562.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280G>C (p.V94L) alteration is located in exon 4 (coding exon 4) of the TMEM54 gene. This alteration results from a G to C substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Polyphen		1.0	D
Vest4		0.11
MutPred		0.48		Loss of sheet (P = 0.0315);
MVP		0.36
MPC		0.28
ClinPred		0.77	D
GERP RS		4.2
Varity_R		0.095
gMVP		0.64
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1641578774; hg19: chr1-33361335;