ENST00000309585.9:c.-351A>C

Variant names:

• chrX-154412069-T-G
• rs62617809
• ENST00000309585.9:c.-351A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000309585.9(DNASE1L1):​c.-351A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,372 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DNASE1L1 ENST00000309585.9 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 8 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.110-17T>G		intron_variant	Intron 1 of 10	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.110-17T>G		intron_variant	Intron 1 of 10	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110716 Hom.: 0 Cov.: 23

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: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095656 Hom.: 0 Cov.: 60 AF XY: 0.00 AC XY: 0 AN XY: 361622

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35071

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 53905

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840944

Other (OTH) AF: 0.00 AC: 0 AN: 45980

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110716 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32922

African (AFR) AF: 0.00 AC: 0 AN: 30482

American (AMR) AF: 0.00 AC: 0 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3468

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5917

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52606

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 5698

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
PhyloP100		-0.27
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62617809; hg19: chrX-153640406;