rs368329470

Variant names:

• chrX-154412099-C-T
• rs368329470
• ENST00000309585.9:c.-381G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The ENST00000309585.9(DNASE1L1):​c.-381G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,208,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: DNASE1L1 ENST00000309585.9 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.632
• Publications: 0 publications found

Genes affected

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]

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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-154412099-C-T is Benign according to our data. Variant chrX-154412099-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 412664.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.123C>T	p.His41His	synonymous_variant	Exon 2 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.123C>T	p.His41His	synonymous_variant	Exon 2 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112292 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000338 AC: 6 AN: 177259 AF XY: 0.0000315

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: 0.0000766

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096435 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 1 AN XY: 362207

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39937

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841511

Other (OTH) AF: 0.00 AC: 0 AN: 46040

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112292 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34454

African (AFR) AF: 0.0000323 AC: 1 AN: 30939

American (AMR) AF: 0.00 AC: 0 AN: 10723

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6241

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53061

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Benign:1

May 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		-0.63
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs368329470; hg19: chrX-153640436;