X-154414191-G-A

Variant names:

• chrX-154414191-G-A
• rs878853655
• NM_000116.5:c.460+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000116.5(TAFAZZIN):​c.460+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,608 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: TAFAZZIN NM_000116.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.45
• 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: ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.102389075 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of -24, new splice context is: cagGTgctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in 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.460+1G>A		splice_donor intron	N/A	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.514+1G>A		splice_donor intron	N/A	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.514+1G>A		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.460+1G>A		splice_donor intron	N/A	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.424+624G>A		intron	N/A	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.295+624G>A		intron	N/A	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000562 AC: 1 AN: 177828 AF XY: 0.00

Gnomad AFR exome AF: 0.0000784

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090608 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 356404

African (AFR) AF: 0.0000381 AC: 1 AN: 26274

American (AMR) AF: 0.00 AC: 0 AN: 34960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19289

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00 AC: 0 AN: 53412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3795

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836531

Other (OTH) AF: 0.00 AC: 0 AN: 45846

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	3-Methylglutaconic aciduria type 2 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Benign	-0.93
CADD	Benign	16
DANN	Benign	0.51
FATHMM_MKL	Benign	0.0059	N
PhyloP100		1.5
GERP RS		-2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.53
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

Other links and lift over

dbSNP: rs878853655; hg19: chrX-153642528;