X-154420037-G-A

Position:

• chrX-154420037-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000116.5(TAFAZZIN):​c.589G>A​(p.Gly197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,088 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Mitochondrial intermembrane (size 226) 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, 0.991
• PP5: Variant X-154420037-G-A is Pathogenic according to our data. Variant chrX-154420037-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154420037-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.589G>A	p.Gly197Arg	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.589G>A	p.Gly197Arg	missense_variant	8/11	1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363458

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2020	This sequence change replaces glycine with arginine at codon 197 of the TAZ protein (p.Gly197Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be hemizygous in several individuals affected with Barth syndrome (PMID: 9382096, 14654353). This variant is also known as G877A in the literature. ClinVar contains an entry for this variant (Variation ID: 11105). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -

TAFAZZIN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 01, 2023

Variant summary: TAZ c.589G>A (p.Gly197Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183500 control chromosomes (gnomAD). c.589G>A has been reported in the literature in multiple individuals affected with Barth Syndrome (e.g. D'Adamo_1997, Bleyl_1997, Cantlay_1999, Ruggolotto_2003, Donati_2006, Alharbi_2022). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

TAFAZZIN: PP1:Strong, PM2, PM5, PS4:Moderate, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	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	3.5	.;.;.;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	.;.;.;.;.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.012	.;.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.;.
Vest4		0.89
MutPred		0.96		.;.;.;.;Gain of MoRF binding (P = 0.0198);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.88
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs132630277; hg19: chrX-153648376;