Genetic Variant NM_000116.5:c.751C>G (chrX-154420709-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000116.5(TAFAZZIN):c.751C>G(p.Arg251Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R251W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56

Publications

8 publications found

Variant links:

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)

TAFAZZIN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAFAZZIN	NM_000116.5	MANE Select	c.751C>G	p.Arg251Gly	missense	Exon 10 of 11	NP_000107.1	Q16635-1
TAFAZZIN	NM_001440856.1		c.805C>G	p.Arg269Gly	missense	Exon 10 of 11	NP_001427785.1
TAFAZZIN	NM_001303465.2		c.763C>G	p.Arg255Gly	missense	Exon 9 of 10	NP_001290394.1	A6XNE1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.751C>G	p.Arg251Gly	missense	Exon 10 of 11	ENSP00000469981.1	Q16635-1
TAFAZZIN	ENST00000475699.6	TSL:1	c.715C>G	p.Arg239Gly	missense	Exon 9 of 10	ENSP00000419854.3	A0A499FJ53
TAFAZZIN	ENST00000369776.8	TSL:1	c.661C>G	p.Arg221Gly	missense	Exon 6 of 7	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-Methylglutaconic aciduria type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.43

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.46

Sift

Benign

0.21

Sift4G

Benign

0.26

Polyphen

0.082

Vest4

0.44

MutPred

0.39

Gain of catalytic residue at P247 (P = 0.0813)

MVP

0.92

ClinPred

0.60

GERP RS

4.8

PromoterAI

-0.082

Neutral

(source)

Varity_R

0.20

gMVP

0.84

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over