NM_000116.5:c.606G>C

Variant names:

• chrX-154420054-G-C
• rs781893396
• NM_000116.5:c.606G>C
• TAFAZZIN p.Glu202Asp

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1 BS1 BS2

The NM_000116.5(TAFAZZIN):​c.606G>C​(p.Glu202Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,098,239 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000021 (0 hom. 9 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000116.5
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000209 (23/1098239) while in subpopulation SAS AF = 0.000425 (23/54147). AF 95% confidence interval is 0.00029. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

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.606G>C	p.Glu202Asp	missense	Exon 8 of 11	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.660G>C	p.Glu220Asp	missense	Exon 8 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.618G>C	p.Glu206Asp	missense	Exon 7 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.606G>C	p.Glu202Asp	missense	Exon 8 of 11	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.570G>C	p.Glu190Asp	missense	Exon 7 of 10	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.399G>C	p.Glu133Asp	missense	Exon 5 of 7	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183505 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

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: 0.0000209 AC: 23 AN: 1098239 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 363601

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.000425 AC: 23 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842133

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 23

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	0.72
BayesDel_addAF	Benign	-0.00039	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.67
Sift	Benign	0.18	T
Sift4G	Benign	0.40	T
PromoterAI		-0.0095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.96
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

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

Other links and lift over

dbSNP: rs781893396;

hg19: chrX-153648393;