X-154413248-C-T

Variant names:

• chrX-154413248-C-T
• rs104894942
• NM_000116.5:c.280C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000116.5(TAFAZZIN):​c.280C>T​(p.Arg94Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.07

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 18 ACMG points.

• PM1: In a chain Tafazzin (size 261) in uniprot entity TAZ_HUMAN there are 38 pathogenic changes around while only 5 benign (88%) in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154413248-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-154413248-C-T is Pathogenic according to our data. Variant chrX-154413248-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154413248-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154413248-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.280C>T	p.Arg94Cys	missense_variant	Exon 3 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.280C>T	p.Arg94Cys	missense_variant	Exon 3 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:2

Feb 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 202092). This missense change has been observed in individual(s) with Barth syndrome (PMID: 9345098, 24342716, 26845103, 28123175). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the TAZ protein (p.Arg94Cys). This variant disrupts the p.Arg94 amino acid residue in TAZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 08, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 06, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg94Cys mutation in the TAZ gene has been reported previously in association with Barth syndrome and was not seen in 50 control X chromosomes (Johnston J et al., 1997). The Arg94Cys mutation was not observed in approximately 5,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Arg94Cys mutation is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The Arg94 residue is highly conserved across species. In silico analysis predicts that Arg94Cys is probably damaging to the protein function/structure. Mutations in the same residue (Arg94Gly, Arg94Ser, Arg94His) have been reported in association with Barth syndrome further supporting the functional importance of this region of the protein. Mutations in the TAZ gene are primarily associated with Barth Syndrome, an X-linked recessive disorder characterized by growth retardation, skeletal myopathy and cardiomyopathy, intermittent lactic academia, neutropenia, and recurrent infection in childhood (Johnston J et al., 1997). TAZ mutations have also been reported in families with X-linked recessive isolated left ventricular non-compaction, and and showed that there was no correlation between either type or position of mutation with cardiac phenotype or severity (Chen R et al., 2002). The variant is found in TAZ panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;.;D;.;D
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;H;.;H;H;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	.;.;D;.;.;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.;.
Vest4		0.80, 0.78, 0.77, 0.74, 0.84
MutPred		0.97		.;Gain of catalytic residue at W95 (P = 0.0014);Gain of catalytic residue at W95 (P = 0.0014);.;Gain of catalytic residue at W95 (P = 0.0014);Gain of catalytic residue at W95 (P = 0.0014);.;Gain of catalytic residue at W95 (P = 0.0014);
MVP		1.0
ClinPred		1.0	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs104894942; hg19: chrX-153641585;