rs397515747

Positions:

• chrX-154420657-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000116.5(TAFAZZIN):​c.700-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.087599546 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154420657-G-A is Pathogenic according to our data. Variant chrX-154420657-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42265.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154420657-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.700-1G>A		splice_acceptor_variant		ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.700-1G>A		splice_acceptor_variant		1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2017

The c.700-1G>A variant in TAZ has been previously reported in one individual wit h a diagnosis and family history of Barth Syndrome (Rigaud 2013). It has also be en identified by our laboratory in the hemizygous state in 2 individuals with cl inical features of Barth Syndrome. This variant occurs in the invariant region ( +/- 1,2) of the splice consensus sequence and is expected to cause altered splic ing, leading to an abnormal or absent protein. Loss of TAZ gene function is an e stablished mechanism for Barth syndrome. In summary, the c.700-1G>A variant meet s criteria to be classified as pathogenic based its presence in multiple affecte d individuals with specific clinical features, extremely low frequency in the ge neral population, and the predicted impact of splicing defect on the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515747; hg19: chrX-153648996;