rs73296180

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001160148.2(DDHD1):c.448G>T(p.Gly150Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,613,028 control chromosomes in the GnomAD database, including 140 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G150G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 61 hom. )

Consequence

DDHD1
NM_001160148.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.89

Publications

2 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 links:

DDHD1-DT (HGNC:55441): (DDHD1 divergent transcript)

DDHD1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021054745).

BP6

Variant 14-53152651-C-A is Benign according to our data. Variant chr14-53152651-C-A is described in ClinVar as Benign. ClinVar VariationId is 381452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2 link	c.448G>T	p.Gly150Cys	missense_variant	Exon 1 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.448G>T	p.Gly150Cys	missense_variant	Exon 1 of 13		NM_001160148.2	ENSP00000500986.2		Q8NEL9-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2632

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00459

AC:

1135

AN:

247476

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.0624

Gnomad AMR exome

AF:

0.00331

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000243

Gnomad OTH exome

AF:

0.00233

GnomAD4 exome

AF:

0.00174

AC:

2547

AN:

1460828

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1110

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.0582

AC:

1949

AN:

33476

American (AMR)

AF:

0.00376

AC:

168

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52632

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1111848

Other (OTH)

AF:

0.00413

AC:

249

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.0173

AC:

2636

AN:

152200

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1229

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0593

AC:

2464

AN:

41522

American (AMR)

AF:

0.00856

AC:

131

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67992

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

118

237

355

474

592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00888

Hom.:

Bravo

AF:

0.0195

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0554

AC:

243

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.00548

AC:

665

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 17, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia

Benign:1

Aug 24, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia 28

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0099

.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.92

L;L;L

PhyloP100

1.9

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.072

Sift

Benign

0.093

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.033, 0.031

.;B;B

Vest4

0.24

MVP

0.043

MPC

0.48

ClinPred

0.013

GERP RS

1.6

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.086

gMVP

0.36

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over