rs727504394

Variant names:

• chrX-154420665-CTG-C
• rs727504394
• NM_000116.5:c.710_711delTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000116.5(TAFAZZIN):​c.710_711delTG​(p.Val237AlafsTer73) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: TAFAZZIN NM_000116.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.50

Genes affected

TAFAZZIN (HGNC:11577): (tafazzin, phospholipid-lysophospholipid transacylase) This gene encodes a protein that is expressed at high levels in cardiac and skeletal muscle. Mutations in this gene have been associated with a number of clinical disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). Multiple transcript variants encoding different isoforms have been described. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154420665-CTG-C is Pathogenic according to our data. Variant chrX-154420665-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 177908.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154420665-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.710_711delTG	p.Val237AlafsTer73	frameshift_variant	Exon 10 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.710_711delTG	p.Val237AlafsTer73	frameshift_variant	Exon 10 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy;C0574083:3-Methylglutaconic aciduria type 2 Pathogenic:1

Jun 21, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Val237fs variant has been reported in the Barth syndrome database although n o clinical data are available (http://www.barthsyndrome.org/). This variant is p redicted to cause a frameshift in the protein's amino acid sequence beginning at codon 237 and altering the remaining 56 amino acids, as well as including an ad ditional 17 amino acids. The severity of this alteration makes it highly likely that this variant is pathogenic. In addition, our laboratory has identified this variant in one proband with features consistent with Barth syndrome. In this pr oband, the variant had occurred de novo, which further supports a pathogenic rol e. In summary, this variant fulfills our pathogenicity criteria based on de novo occurrence, predicted impact of the variant on the protein as well as consisten cy of this individual?s clinical presentation with the presence of a TAZ variant . -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504394; hg19: chrX-153649004;