Genetic Variant DDHD1:c.*3370_*3375dupACACAC (chr14-53043392-A-AGTGTGT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001160148.2(DDHD1):c.*3370_*3375dupACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.25 ( 2662 hom., cov: 0)

Exomes 𝑓: 0.045 ( 0 hom. )

Consequence

DDHD1
NM_001160148.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Publications

1 publications found

Variant links:

Genes affected

DDHD1 (HGNC:19714): (DDHD domain containing 1) This gene is a member of the intracellular phospholipase A1 gene family. The protein encoded by this gene preferentially hydrolyzes phosphatidic acid. It is a cytosolic protein with some mitochondrial localization, and is thought to be involved in the regulation of mitochondrial dynamics. Overexpression of this gene causes fragmentation of the tubular structures in mitochondria, while depletion of the gene results in mitochondrial tubule elongation. Deletion of this gene in male mice caused fertility defects, resulting from disruption in the organization of the mitochondria during spermiogenesis. In humans, mutations in this gene have been associated with hereditary spastic paraplegia (HSP), also known as Strumpell-Lorrain disease, or, familial spastic paraparesis (FSP). This inherited disorder is characterized by progressive weakness and spasticity of the legs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

DDHD1 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 28
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

DDHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2 link	c.3370_3375dupACACAC		3_prime_UTR_variant	Exon 13 of 13	ENST00000673822.2	NP_001153620.1	Q8NEL9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2 link	c.3370_3375dupACACAC		3_prime_UTR_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2		Q8NEL9-1
DDHD1	ENST00000395606.5 link	c.3370_3375dupACACAC		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000378970.1		Q8NEL9-4

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

27615

AN:

111992

Hom.:

2660

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.247

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.202

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.262

GnomAD4 exome

AF:

0.0455

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0714

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.247

AC:

27633

AN:

112078

Hom.:

2662

Cov.:

AF XY:

0.250

AC XY:

13442

AN XY:

53788

show subpopulations

African (AFR)

AF:

0.256

AC:

9259

AN:

36208

American (AMR)

AF:

0.319

AC:

3521

AN:

11054

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

685

AN:

2760

East Asian (EAS)

AF:

0.387

AC:

1372

AN:

3548

South Asian (SAS)

AF:

0.294

AC:

828

AN:

2816

European-Finnish (FIN)

AF:

0.209

AC:

1187

AN:

5674

Middle Eastern (MID)

AF:

0.201

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.214

AC:

10148

AN:

47524

Other (OTH)

AF:

0.264

AC:

414

AN:

1566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

926

1852

2778

3704

4630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0830

Hom.:

108

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Jan 24, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Splicing

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

Publications

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14-53043392-A-AGTGTGT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over