rs200405157

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000116.5(TAFAZZIN):c.331C>T(p.His111Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000628 in 1,211,097 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000067 ( 0 hom. 24 hem. )

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

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

BP4

Computational evidence support a benign effect (MetaRNN=0.11993778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5 linkuse as main transcript	c.331C>T	p.His111Tyr	missense_variant	4/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6 linkuse as main transcript	c.331C>T	p.His111Tyr	missense_variant	4/11	1	NM_000116.5		Q16635-1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112929

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35079

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183323

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67837

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000674

AC:

AN:

1098168

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

363542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000879

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112929

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35079

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 04, 2013

The His111Tyr variant in TAZ has not been reported in any other families with ca rdiomyopathy, but has been identified in 1/6728 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs 200405157). Computational analyses (biochemical amino acid properties, conservat ion, AlignGVGD, PolyPhen2, and SIFT) suggest that the His111Tyr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional studies are needed to fully assess the clinical sign ificance of the His111Tyr variant. -

3-Methylglutaconic aciduria type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 111 of the TAZ protein (p.His111Tyr). This variant is present in population databases (rs200405157, gnomAD 0.008%). This missense change has been observed in individual(s) with left ventricular noncompaction cardiomyopathy (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 165328). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The p.H111Y variant (also known as c.331C>T), located in coding exon 4 of the TAZ gene, results from a C to T substitution at nucleotide position 331. The histidine at codon 111 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in left ventricular non-compaction (LVNC) cohorts; however, clinical details were limited (Richard P et al. Clin Genet, 2019 03;95:356-367; Mazzarotto F et al. Genet Med, 2021 05;23:856-864). Based on data from gnomAD, the T allele has an overall frequency of 0.0029% (6/205368) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0065% (6/92637) of European (non-Finnish) alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Benign

0.81

FATHMM_MKL

Benign

0.097

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.45

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0, 0.30

.;B;B;.;B;B;.;.

Vest4

0.37, 0.35, 0.38, 0.31, 0.36

MVP

0.70

ClinPred

0.053

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over