TAFAZZIN p.Asp219Glu

Variant names:

• chrX-154420222-C-A
• NM_000116.5:c.657C>A
• TAFAZZIN p.Asp219Glu

Your query was ambiguous. Multiple possible variants found:

• chrX-154420222-C-A
• chrX-154420222-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000116.5(TAFAZZIN):​c.657C>A​(p.Asp219Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D219D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.943
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41529918).

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.657C>A	p.Asp219Glu	missense	Exon 9 of 11	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.711C>A	p.Asp237Glu	missense	Exon 9 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.669C>A	p.Asp223Glu	missense	Exon 8 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.657C>A	p.Asp219Glu	missense	Exon 9 of 11	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.621C>A	p.Asp207Glu	missense	Exon 8 of 10	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.567C>A	p.Asp189Glu	missense	Exon 5 of 7	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
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	3.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.42	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.94
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.58
Sift	Benign	0.36	T
Sift4G	Benign	0.30	T
PromoterAI		-0.29	Neutral
Varity_R		0.16
gMVP		0.88
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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-153648561;