rs146934311

Positions:

• chrX-154414113-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 11/19 in silico tools predict 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.303

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 Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Mitochondrial intermembrane (size 226) in uniprot entity TAZ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 [Likely_benign]. Clinvar id is 42259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154414113-T-C is described in Lovd as [Benign]. Variant chrX-154414113-T-C is described in Lovd as [Likely_benign]. Variant chrX-154414113-T-C is described in Lovd as [Likely_pathogenic].
• 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/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.383T>C	p.Phe128Ser	missense_variant	5/11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.383T>C	p.Phe128Ser	missense_variant	5/11	1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 1786 AN: 110076 Hom.: 28 Cov.: 23 AF XY: 0.0128 AC XY: 414 AN XY: 32332

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

GnomAD3 exomes AF: 0.00457 AC: 831 AN: 182022 Hom.: 13 AF XY: 0.00275 AC XY: 183 AN XY: 66664

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 SAS exome AF: 0.0000534

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.: 36 Cov.: 29 AF XY: 0.00142 AC XY: 511 AN XY: 359485

Gnomad4 AFR exome AF: 0.0592

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.0162 AC: 1783 AN: 110134 Hom.: 28 Cov.: 23 AF XY: 0.0128 AC XY: 414 AN XY: 32400

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.00553

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000152

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00344 Hom.: 38

Bravo AF: 0.0191

ESP6500AA AF: 0.0524 AC: 201

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00535 AC: 650

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 27884173, 19700766, 24342716, 19438153, 20530761) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

3-Methylglutaconic aciduria type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2015

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	6.1
DANN	Benign	0.88
DEOGEN2	Benign	0.31	.;.;T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.35	.;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.6	.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
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	T
GERP RS		-0.54
Varity_R		0.13
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs146934311; hg19: chrX-153642450;