rs191527230

Positions:

• chrX-154420108-C-T

Variant summary

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

The ENST00000369776.8(TAFAZZIN):​c.453C>T​(p.Asp151=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,209,512 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 101 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 0.0019 (0 hom., 50 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (0 hom. 51 hem.)
• Consequence: TAFAZZIN ENST00000369776.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.19

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=-0.92).
• BP6: Variant X-154420108-C-T is Benign according to our data. Variant chrX-154420108-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154420108-C-T is described in Lovd as [Benign]. Variant chrX-154420108-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 50 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.646+14C>T		intron_variant		ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.646+14C>T		intron_variant		1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 211 AN: 111968 Hom.: 0 Cov.: 23 AF XY: 0.00146 AC XY: 50 AN XY: 34192

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000643 AC: 118 AN: 183439 Hom.: 0 AF XY: 0.000339 AC XY: 23 AN XY: 67883

Gnomad AFR exome AF: 0.00707

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000721

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000199 AC: 218 AN: 1097489 Hom.: 0 Cov.: 31 AF XY: 0.000141 AC XY: 51 AN XY: 362879

Gnomad4 AFR exome AF: 0.00614

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000364

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.000347

GnomAD4 genome AF: 0.00188 AC: 211 AN: 112023 Hom.: 0 Cov.: 23 AF XY: 0.00146 AC XY: 50 AN XY: 34257

Gnomad4 AFR AF: 0.00658

Gnomad4 AMR AF: 0.000281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000565

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.000656

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.00212

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2013	646+14C>T in intron 8 of TAZ: This variant is not expected to have clinical sign ificance because it is not located within the conserved splice consensus sequenc e. It has been identified in 0.8% (32/3835) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washing ton.edu/EVS; dbSNP rs191527230). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2019	Variant summary: TAZ c.646+14C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00064 in 183439 control chromosomes, predominantly at a frequency of 0.0071 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TAZ causing Barth Syndrome phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.646+14C>T in individuals affected with Barth Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar before 2014 and have settled on a classification as benign. Based on the evidence outlined above, the variant was classified as benign. -

3-Methylglutaconic aciduria type 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

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. -

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	-0.92
CADD	Benign	0.033
DANN	Benign	0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs191527230; hg19: chrX-153648447;