X-154411856-G-T

Position:

chrX-154411856-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000116.5(TAFAZZIN):c.13G>T(p.Val5Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,197,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 1 hem. )

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.63

Variant links:

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 links:

DNASE1L1 (HGNC:2957): (deoxyribonuclease 1 like 1) This gene encodes a deoxyribonuclease protein that shows high sequence similarity to DNase I. The encoded protein is localized to the endoplasmic reticulum and modified by N-linked glycosylation. Alternate transcriptional splice variants encoding the same protein have been observed. [provided by RefSeq, Jan 2015]

DNASE1L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Tafazzin (size 261) in uniprot entity TAZ_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000116.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5 linkuse as main transcript	c.13G>T	p.Val5Leu	missense_variant	1/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6 linkuse as main transcript	c.13G>T	p.Val5Leu	missense_variant	1/11	1	NM_000116.5		Q16635-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112372

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34538

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000753

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000339

AC:

AN:

147643

Hom.:

AF XY:

0.00

AC XY:

AN XY:

47991

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000739

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1084998

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

356184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000783

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112372

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34538

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000753

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 07, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Val5Leu var iant has not been reported in the literature but has been identified in an Ashke nazi Jewish individual with mild DCM and muscle weakness as well as two family m embers (brother and mother) with similar features. The variant was absent from 332 Ashkenazi Jewish control chromosomes, which is consistent with a pathogenic role (LMM unpublished data). Valine (Val) at position 5 is conserved across mamm als and amphibians, but is not 100% conserved across more evolutionary distant s pecies (fruitfly and yeast), reducing the likelihood that the change is pathogen ic. Valine and Leucine have similar biochemical properties, which also suggest t hat the change may not severely affect the protein. However, most TAZ variants a re pathogenic and cause Barth syndrome (www.barthsyndrome.org). In summary, thi s variant likely causes or contributes to disease but additional data is needed to establish this with certainty. Please note that a new biochemical test is ava ilable that can help establish a diagnosis of Barth syndrome (see recommendation s section). -

3-Methylglutaconic aciduria type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the TAZ protein (p.Val5Leu). This variant is present in population databases (rs397515737, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with TAZ-related conditions. ClinVar contains an entry for this variant (Variation ID: 42253). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2017

A variant of uncertain significance has been identified in the TAZ gene. The V5L variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory, where it was observed in an Ashkenazi Jewish individual with mild DCM and muscle weakness, and segregated with similar features in this individual's mother and brother (ClinVar SCV000058726.4; Landrum et al., 2016). The V5L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V5L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this variant lacks observation in a significant number of affected individuals, large segregation studies, and functional evidence, which would further clarify its pathogenicity. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

The p.V5L variant (also known as c.13G>T), located in coding exon 1 of the TAZ gene, results from a G to T substitution at nucleotide position 13. The valine at codon 5 is replaced by leucine, an amino acid with highly similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.00387% (5/147643) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.07389% (5/6767) of Ashkenazi Jewish alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.84

Sift4G

Benign

0.15

T;T;T;T;T;T;T;T

Polyphen

1.0, 0.83, 0.98, 1.0

.;D;P;.;D;D;.;.

Vest4

0.48, 0.49, 0.50, 0.39, 0.53

MutPred

0.48

Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);Gain of catalytic residue at V5 (P = 0.0346);

MVP

0.96

ClinPred

0.42

GERP RS

4.3

Varity_R

0.45

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over