X-154411870-C-G

Position:

chrX-154411870-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_000116.5(TAFAZZIN):c.27C>G(p.Phe9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,201,304 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.50

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 Likely_benign. 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 4 benign (90%) in NM_000116.5

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5 linkuse as main transcript	c.27C>G	p.Phe9Leu	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.27C>G	p.Phe9Leu	missense_variant	1/11	1	NM_000116.5		Q16635-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112266

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

34436

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1089038

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

358046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

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:

0.0000437

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112266

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

34436

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-Methylglutaconic aciduria type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 9 of the TAZ protein (p.Phe9Leu). This variant is not present in population databases (gnomAD no frequency). 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: 840746). 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2020

The p.F9L variant (also known as c.27C>G), located in coding exon 1 of the TAZ gene, results from a C to G substitution at nucleotide position 27. The phenylalanine at codon 9 is replaced by leucine, an amino acid with highly similar properties. 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

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

.;.;.;.;.;T;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;T;T;.;T;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.73

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.6

.;L;L;.;L;L;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.3

.;.;D;.;.;.;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.079

.;.;T;.;.;.;T;T

Sift4G

Benign

0.15

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

Polyphen

0.12, 0.17, 0.23, 0.98

.;B;B;.;B;D;.;.

Vest4

0.44, 0.42, 0.58, 0.47, 0.50

MutPred

0.81

Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);Gain of glycosylation at P14 (P = 0.0722);

MVP

0.83

ClinPred

0.94

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.79

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