X-154413507-T-C

Position:

• chrX-154413507-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000601016.6(TAFAZZIN):​c.310T>C​(p.Phe104Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F104V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: TAFAZZIN ENST00000601016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.19

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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000601016.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154413507-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant X-154413507-T-C is Pathogenic according to our data. Variant chrX-154413507-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42257.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chrX-154413507-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.310T>C	p.Phe104Leu	missense_variant	4/11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.310T>C	p.Phe104Leu	missense_variant	4/11	1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

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

Mar 15, 2012

The Phe104Leu variant (TAZ) has not been previously reported, but appears to hav e occurred de novo in 1 individual with clinical features of Barth syndrome test ed by our laboratory. Phenylalanine (Phe) is highly conserved across evolutionar ily distant species, increasing the likelihood that a change would not be tolera ted. Computational tools (PolyPhen2, SIFT) predict that a change to Leu would im pact the protein, though the accuracy of these tools is unknown. Another variant at the same position (Phe104Val) has been reported as occurring de novo in 1 in dividual with elevated MLCL levels (Tafazzin (TAZ) Gene Mutation Database) and y east constructs of this variant resulted in a significant accumulation of MLCLs (Claypool 2011). Collectively, this information supports that the Phe104Leu vari ant is highly likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;.;.;D;.;D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	.;.;D;.;.;.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D
Sift4G	Uncertain	0.0050	D;D;T;D;T;D;D;D
Polyphen		0.58, 0.92, 0.92, 0.91	.;P;P;.;P;P;.;.
Vest4		0.88, 0.82, 0.79, 0.76, 0.82
MutPred		0.89		.;Gain of catalytic residue at F104 (P = 0.0078);Gain of catalytic residue at F104 (P = 0.0078);.;Gain of catalytic residue at F104 (P = 0.0078);Gain of catalytic residue at F104 (P = 0.0078);.;Gain of catalytic residue at F104 (P = 0.0078);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.99

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: rs397515741; hg19: chrX-153641844;