rs397515746

Positions:

• chrX-154420038-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000116.5(TAFAZZIN):​c.590G>A​(p.Gly197Glu) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.36

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]

TAFAZZIN (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Tafazzin (size 261) in uniprot entity TAZ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-154420038-G-A is Pathogenic according to our data. Variant chrX-154420038-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42264.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chrX-154420038-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.590G>A	p.Gly197Glu	missense_variant	8/11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.590G>A	p.Gly197Glu	missense_variant	8/11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 25, 2020	This sequence change replaces glycine with glutamic acid at codon 197 of the TAZ protein (p.Gly197Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutatmic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Barth syndrome (PMID: 9345098). ClinVar contains an entry for this variant (Variation ID: 42264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). This variant disrupts the p.Gly197 amino acid residue in TAZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9382096, 23656970, 14654353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2012	The Gly197Glu variant in TAZ has been reported in one male infant with clinical features of Barth syndrome and a family history of disease that is consistent wi th X-linked inheritance (Kelley 1991, Johnston 1997). This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to esta blish this with confidence. Computational analyses (biochemical amino acid prope rties, conservation, PolyPhen2, and SIFT) suggest that this variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. Finally, the majority of TAZ variants are pathogenic (www.barthsyndrome .org) and other variants at this position (Gly197Arg, Gly197Trp, Gly197Val) have been reported in individual's the Barth syndrome. In summary, this variant is l ikely to be pathogenic, though additional studies are required to fully establis h its clinical significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	.;.;.;.;.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.015	.;.;.;.;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.;.
Vest4		0.91
MutPred		0.94		.;.;.;.;Loss of methylation at R198 (P = 0.0445);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.92
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs397515746; hg19: chrX-153648377;