ENST00000309585.9:c.-173G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP3_ModerateBP6_Very_StrongBS2

The ENST00000309585.9(DNASE1L1):c.-173G>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,205,714 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. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

DNASE1L1
ENST00000309585.9 splice_region

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.652

Publications

1 publications found

Variant links:

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]

DNASE1L1 links:

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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen

TAFAZZIN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000309585.9, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP3

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

BP6

Variant X-154411891-C-G is Benign according to our data. Variant chrX-154411891-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 42260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000309585.9. 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.48C>G	p.Thr16Thr	synonymous	Exon 1 of 11	NP_000107.1	Q16635-1
DNASE1L1	NM_001009932.3		c.-431G>C		splice_region	Exon 1 of 10	NP_001009932.1	P49184
DNASE1L1	NM_001009933.3		c.-173G>C		splice_region	Exon 1 of 9	NP_001009933.1	P49184

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNASE1L1	ENST00000309585.9	TSL:1	c.-173G>C		splice_region	Exon 1 of 9	ENSP00000309168.5	P49184
TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.48C>G	p.Thr16Thr	synonymous	Exon 1 of 11	ENSP00000469981.1	Q16635-1
TAFAZZIN	ENST00000475699.6	TSL:1	c.48C>G	p.Thr16Thr	synonymous	Exon 1 of 10	ENSP00000419854.3	A0A499FJ53

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112350

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000605

AC:

AN:

165304

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000857

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1093364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360532

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26359

American (AMR)

AF:

0.00

AC:

AN:

35028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19291

East Asian (EAS)

AF:

0.00

AC:

AN:

30109

South Asian (SAS)

AF:

0.00

AC:

AN:

53671

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38105

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840820

Other (OTH)

AF:

0.00

AC:

AN:

45891

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112350

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

34516

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

31008

American (AMR)

AF:

0.00

AC:

AN:

10794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3541

South Asian (SAS)

AF:

0.00

AC:

AN:

2744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6209

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52968

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-Methylglutaconic aciduria type 2 (1)

Cardiovascular phenotype (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.65

PromoterAI

-0.075

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=265/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over