X-154413507-T-G

Variant names:

• chrX-154413507-T-G
• rs397515741
• NM_000116.5:c.310T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000116.5(TAFAZZIN):​c.310T>G​(p.Phe104Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F104L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154413507-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42257.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

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.310T>G	p.Phe104Val	missense	Exon 4 of 11	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.364T>G	p.Phe122Val	missense	Exon 4 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.364T>G	p.Phe122Val	missense	Exon 4 of 10	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.310T>G	p.Phe104Val	missense	Exon 4 of 11	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.364T>G	p.Phe122Val	missense	Exon 4 of 10	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.235T>G	p.Phe79Val	missense	Exon 3 of 7	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-Methylglutaconic aciduria type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.92		Loss of helix (P = 0.1299)
MVP		1.0
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs397515741; hg19: chrX-153641844;