Genetic Variant TAFAZZIN:p.Gly80Arg (chrX-154412214-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000116.5(TAFAZZIN):c.238G>A(p.Gly80Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/27 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

TAFAZZIN
NM_000116.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.89

Publications

0 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 links:

DNASE1L1 (HGNC:2957): (deoxyribonuclease 1 like 1) This gene encodes a deoxyribonuclease protein that shows high sequence similarity to DNase I. The encoded protein is localized to the endoplasmic reticulum and modified by N-linked glycosylation. Alternate transcriptional splice variants encoding the same protein have been observed. [provided by RefSeq, Jan 2015]

DNASE1L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000116.5

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-154412214-G-A is Pathogenic according to our data. Variant chrX-154412214-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 531184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.238G>A	p.Gly80Arg	missense splice_region	Exon 2 of 11	NP_000107.1	Q16635-1
TAFAZZIN	NM_001440856.1		c.292G>A	p.Gly98Arg	missense splice_region	Exon 2 of 11	NP_001427785.1
TAFAZZIN	NM_001303465.2		c.292G>A	p.Gly98Arg	missense splice_region	Exon 2 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.238G>A	p.Gly80Arg	missense splice_region	Exon 2 of 11	ENSP00000469981.1	Q16635-1
TAFAZZIN	ENST00000475699.6	TSL:1	c.292G>A	p.Gly98Arg	missense splice_region	Exon 2 of 10	ENSP00000419854.3	A0A499FJ53
TAFAZZIN	ENST00000612460.5	TSL:1	c.238G>A	p.Gly80Arg	missense splice_region	Exon 2 of 10	ENSP00000481037.1	Q16635-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1081884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352488

African (AFR)

AF:

0.00

AC:

AN:

26185

American (AMR)

AF:

0.00

AC:

AN:

33241

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18994

East Asian (EAS)

AF:

0.00

AC:

AN:

29667

South Asian (SAS)

AF:

0.00

AC:

AN:

52141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38589

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833501

Other (OTH)

AF:

0.00

AC:

AN:

45450

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-Methylglutaconic aciduria type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.76

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

8.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.88

MutPred

0.81

Gain of MoRF binding (P = 0.029)

MVP

1.0

ClinPred

1.0

GERP RS

4.0

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

1.0

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.33

Position offset: 36

DS_DL_spliceai

0.62

Position offset: 0

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