rs132630277

Variant names:

• chrX-154420037-G-A
• rs132630277
• NM_000116.5:c.589G>A

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.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. 12/21 in silico tools predict a damaging 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. G197E) has been classified as Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.36
• Publications: 19 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-154420038-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42264.
• 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/Likely_pathogenic. ClinVar VariationId is 11105.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.589G>A	p.Gly197Arg	missense_variant	Exon 8 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.589G>A	p.Gly197Arg	missense_variant	Exon 8 of 11	1	NM_000116.5	ENSP00000469981.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842004

Other (OTH) AF: 0.00 AC: 0 AN: 46091

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000728 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:3

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 197 of the TAZ protein (p.Gly197Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Barth syndrome (PMID: 9382096, 14654353). This variant is also known as G877A. ClinVar contains an entry for this variant (Variation ID: 11105). 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. For these reasons, this variant has been classified as Pathogenic. -

Jul 21, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Nov 18, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 8042670, 20812380, 9345098, 35104856, 14654353, 25525159, 19648820, 10484795, 9382097, 9382096, 32600061, 16906470, 37549445) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

TAFAZZIN-related disorder Pathogenic:1

Mar 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;.;.
PhyloP100		9.4
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
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.88
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs132630277; hg19: chrX-153648376;