X-154419625-G-C

Variant names:

• chrX-154419625-T-C
• NM_000116.5:c.541+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000116.5(TAFAZZIN):​c.541+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.092150174 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000116.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	NM_000116.5	MANE Select	c.541+2T>C		splice_donor intron	N/A	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.595+2T>C		splice_donor intron	N/A	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.595+2T>C		splice_donor intron	N/A	NP_001290394.1	A6XNE1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.541+2T>C		splice_donor intron	N/A	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.505+2T>C		splice_donor intron	N/A	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.376+2T>C		splice_donor intron	N/A	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Benign	0.97
FATHMM_MKL	Benign	0.70	D
PhyloP100		5.6
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -21
DS_DL_spliceai		0.95		Position offset: -2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-153647964;