NM_000116.5:c.383T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000116.5(TAFAZZIN):c.383T>C(p.Phe128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,204,023 control chromosomes in the GnomAD database, including 64 homozygotes. There are 925 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 28 hom., 414 hem., cov: 23)

Exomes 𝑓: 0.0017 ( 36 hom. 511 hem. )

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.303

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Barth syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

TAFAZZIN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000116.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0038991868).

BP6

Variant X-154414113-T-C is Benign according to our data. Variant chrX-154414113-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5 link	c.383T>C	p.Phe128Ser	missense_variant	Exon 5 of 11	ENST00000601016.6	NP_000107.1	Q16635-1A0A0S2Z4K0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6 link	c.383T>C	p.Phe128Ser	missense_variant	Exon 5 of 11	1	NM_000116.5	ENSP00000469981.1		Q16635-1

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

1786

AN:

110076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0563

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00554

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:

0.000152

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00457

AC:

831

AN:

182022

AF XY:

0.00275

show subpopulations

Gnomad AFR exome

AF:

0.0568

Gnomad AMR exome

AF:

0.00245

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00172

AC:

1881

AN:

1093889

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

511

AN XY:

359485

show subpopulations

African (AFR)

AF:

0.0592

AC:

1559

AN:

26317

American (AMR)

AF:

0.00284

AC:

100

AN:

35177

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19346

East Asian (EAS)

AF:

0.00

AC:

AN:

30175

South Asian (SAS)

AF:

0.0000556

AC:

AN:

53923

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40486

Middle Eastern (MID)

AF:

0.00222

AC:

AN:

4049

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

838477

Other (OTH)

AF:

0.00357

AC:

164

AN:

45939

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0162

AC:

1783

AN:

110134

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

414

AN XY:

32400

show subpopulations

African (AFR)

AF:

0.0561

AC:

1692

AN:

30181

American (AMR)

AF:

0.00553

AC:

AN:

10309

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3491

South Asian (SAS)

AF:

0.00

AC:

AN:

2548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000152

AC:

AN:

52724

Other (OTH)

AF:

0.0175

AC:

AN:

1487

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00344

Hom.:

Bravo

AF:

0.0191

ESP6500AA

AF:

0.0524

AC:

201

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00535

AC:

650

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 12, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe128Ser in exon 5 of TAZ: This variant is not expected to have clinical signif icance because it has been identified in 5.1% (165/3215) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs146934311). -

Apr 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 19700766, 24342716, 19438153, 20530761) -

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3-Methylglutaconic aciduria type 2

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Left ventricular noncompaction cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype

Benign:1

Nov 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Endocardial fibroelastosis

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.13

CADD

Benign

6.1

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.31

.;.;T

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.35

.;T;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.6

.;L;L

PhyloP100

0.30

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.8

.;D;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0090

.;D;.

Sift4G

Uncertain

0.045

D;T;T

Polyphen

0.0, 0.0010

.;B;B

Vest4

0.29, 0.086

MVP

0.68

ClinPred

0.0088

GERP RS

-0.54

Varity_R

0.13

gMVP

0.95

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over