X-154413249-G-T

Variant names:

• chrX-154413249-G-T
• rs1060500044
• NM_000116.5:c.281G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000116.5(TAFAZZIN):​c.281G>T​(p.Arg94Leu) variant causes a missense change. 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: 24)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.11
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Barth syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11110.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-154413249-G-T is Pathogenic according to our data. Variant chrX-154413249-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 403954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.281G>T	p.Arg94Leu	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.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:2

Jul 08, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed to be de novo in an individual with cardiomyopathy (Invitae). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Two different missense substitution at this codon (p.Arg94His and p.Arg94Ser) have been determined to be pathogenic (PMID: 23656970, 16548007, 12032589, 23656970). This suggests that the arginine residue is critical for TAZ protein function and that other missense substitutions at this position may also be pathogenic. Furthermore, two additional variants of uncertain significance at this codon (p.Arg94Gly and p.Arg94Cys) have been observed in individuals with Barth syndrome (PMID: 20812380, 9345098). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 94 of the TAZ protein (p.Arg94Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;.;.;.;D;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;M;.;M;M;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;.;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.99, 1.0, 1.0, 0.84	.;D;D;.;D;P;.;.
Vest4		0.90, 0.91, 0.83, 0.85, 0.96
MutPred		0.93		.;Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);.;Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);.;Loss of MoRF binding (P = 0.0176);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.027	Neutral
Varity_R		0.96
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1060500044; hg19: chrX-153641586;