rs1557191170

chrX-154412214-G-AchrX-154412214-G-C

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.238G>A(p.Gly80Arg) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TAFAZZIN NM_000116.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.89

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-154412214-G-A is Pathogenic according to our data. Variant chrX-154412214-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 531184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154412214-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5	c.238G>A	p.Gly80Arg	missense_variant, splice_region_variant	2/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.238G>A	p.Gly80Arg	missense_variant, splice_region_variant	2/11	1	NM_000116.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1081884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 352488

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 08, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 24342716). Experimental studies have shown that this variant affects TAZ function (PMID: 21300850). 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: 531184). This variant has been observed in individual(s) with Barth syndrome (PMID: 24342716). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 80 of the TAZ mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TAZ protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 22, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Pathogenic	37
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.
Vest4		0.88, 0.86, 0.85
MutPred		0.81		.;Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);.;Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 36
DS_DL_spliceai		0.62		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557191170; hg19: chrX-153640551;