14-53152963-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001160148.2(DDHD1):c.136G>A(p.Gly46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,585,200 control chromosomes in the GnomAD database, including 234 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G46C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 12 hom., cov: 32)

Exomes 𝑓: 0.015 ( 222 hom. )

Consequence

DDHD1
NM_001160148.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.308

Publications

3 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=0.0020691454).

BP6

Variant 14-53152963-C-T is Benign according to our data. Variant chr14-53152963-C-T is described in ClinVar as Benign. ClinVar VariationId is 238597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1891/152014) while in subpopulation NFE AF = 0.0177 (1201/67916). AF 95% confidence interval is 0.0169. There are 12 homozygotes in GnomAd4. There are 884 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2 link	c.136G>A	p.Gly46Ser	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.136G>A	p.Gly46Ser	missense_variant	Exon 1 of 13		NM_001160148.2	ENSP00000500986.2		Q8NEL9-1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1893

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0222

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.0128

AC:

2409

AN:

188366

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.0294

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0149

AC:

21387

AN:

1433186

Hom.:

222

Cov.:

AF XY:

0.0146

AC XY:

10386

AN XY:

710698

show subpopulations

African (AFR)

AF:

0.00210

AC:

AN:

32400

American (AMR)

AF:

0.00619

AC:

248

AN:

40052

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

754

AN:

25376

East Asian (EAS)

AF:

0.0000263

AC:

AN:

38000

South Asian (SAS)

AF:

0.00302

AC:

251

AN:

83040

European-Finnish (FIN)

AF:

0.0208

AC:

1043

AN:

50150

Middle Eastern (MID)

AF:

0.0148

AC:

AN:

4456

European-Non Finnish (NFE)

AF:

0.0164

AC:

18085

AN:

1100514

Other (OTH)

AF:

0.0147

AC:

871

AN:

59198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1434

2868

4301

5735

7169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.0124

AC:

1891

AN:

152014

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

884

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00323

AC:

134

AN:

41484

American (AMR)

AF:

0.0102

AC:

156

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00394

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0222

AC:

235

AN:

10590

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0177

AC:

1201

AN:

67916

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0145

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00423

AC:

ESP6500EA

AF:

0.0170

AC:

138

ExAC

AF:

0.0109

AC:

1254

Asia WGS

AF:

0.00202

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 29, 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

Nov 25, 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

Feb 03, 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

0.075

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0060

.;.;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;L;L

PhyloP100

0.31

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.060

.;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.34

.;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.0040, 0.0030

.;.;B;B

Vest4

0.032

MPC

0.44

ClinPred

0.0086

GERP RS

1.6

PromoterAI

0.034

Neutral

(source)

Varity_R

0.073

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(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