rs397515749

Variant names:

• chrX-154420879-GCCATCCCTGGTCCTTTC-A
• rs397515749
• NM_000116.5:c.778-24_778-7delGCCATCCCTGGTCCTTTCinsA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000116.5(TAFAZZIN):​c.778-24_778-7delGCCATCCCTGGTCCTTTCinsA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.638

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.778-24_778-7delGCCATCCCTGGTCCTTTCinsA		splice_region_variant, intron_variant	Intron 10 of 10	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.778-24_778-7delGCCATCCCTGGTCCTTTCinsA		splice_region_variant, intron_variant	Intron 10 of 10	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The 778-24_778- 7delinsA variant has not been reported in the literature and has not been previo usly detected in 369 Caucasian individuals tested by our laboratory. This varian t affects a region that is part of the splicing consensus sequence (-3 and -5 to -12) computational analyses predict that it affects splicing of exon 11. Howeve r, these tools are not predictive enough to assume pathogenicity and further mRN A studies are needed to confirm this. Pathogenic splice variants are common in t he TAZ gene (http://www.barthsyndrome.org) and the presence of a TAZ variant is consistent with this individual?s clinical presentation and family history. In summary, it is very likely that the 778-24_778-7delinsA variant is causative or at least contributory to disease but additional studies are necessary to determi ne its significance with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/100	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515749; hg19: chrX-153649218;