rs35902788

Positions:

• chrX-154420998-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000116.5(TAFAZZIN):​c.873G>A​(p.Gly291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,207,772 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,697 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 0.0037 (2 hom., 102 hem., cov: 23)
  • Exomes 𝑓: 0.0046 (8 hom. 1595 hem.)
• Consequence: TAFAZZIN NM_000116.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.100

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-154420998-G-A is Benign according to our data. Variant chrX-154420998-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154420998-G-A is described in Lovd as [Benign]. Variant chrX-154420998-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.1 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5	c.873G>A	p.Gly291=	synonymous_variant	11/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.873G>A	p.Gly291=	synonymous_variant	11/11	1	NM_000116.5

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 411 AN: 112248 Hom.: 2 Cov.: 23 AF XY: 0.00296 AC XY: 102 AN XY: 34404

Gnomad AFR AF: 0.000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00211

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00464

GnomAD3 exomes AF: 0.00359 AC: 653 AN: 181887 Hom.: 0 AF XY: 0.00347 AC XY: 231 AN XY: 66559

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.000671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00618

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00458 AC: 5014 AN: 1095471 Hom.: 8 Cov.: 30 AF XY: 0.00442 AC XY: 1595 AN XY: 360867

Gnomad4 AFR exome AF: 0.000721

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.000465

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00541

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.00366 AC: 411 AN: 112301 Hom.: 2 Cov.: 23 AF XY: 0.00296 AC XY: 102 AN XY: 34467

Gnomad4 AFR AF: 0.000645

Gnomad4 AMR AF: 0.00535

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00211

Gnomad4 NFE AF: 0.00582

Gnomad4 OTH AF: 0.00459

Alfa AF: 0.00524 Hom.: 127

Bravo AF: 0.00366

EpiCase AF: 0.00583

EpiControl AF: 0.00499

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2012	Gly291Gly in exon 11 of TAZ: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and has been identified in 0.6% (33/5545) of European American chromosomes in a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs359027 88). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2020	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

3-Methylglutaconic aciduria type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2016

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.57

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: rs35902788; hg19: chrX-153649337;