dbSNP rs367621941: DDHD1:p.Gly52Gly (chr14-53152943-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001160148.2(DDHD1):c.156C>T(p.Gly52Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,596,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

DDHD1
NM_001160148.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.52

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 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 14-53152943-G-A is Benign according to our data. Variant chr14-53152943-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415256.

BP7

Synonymous conserved (PhyloP=1.52 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000757 (115/151956) while in subpopulation AMR AF = 0.00222 (34/15292). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160148.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD1	NM_001160148.2	MANE Select	c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
DDHD1	NM_001160147.2		c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
DDHD1	NM_030637.3		c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 12	NP_085140.2	Q8NEL9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDHD1	ENST00000673822.2	MANE Select	c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
DDHD1	ENST00000357758.3	TSL:1	c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
DDHD1	ENST00000907176.1		c.156C>T	p.Gly52Gly	synonymous	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes

AF:

0.000757

AC:

115

AN:

151840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000927

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000629

AC:

131

AN:

208346

AF XY:

0.000697

show subpopulations

Gnomad AFR exome

AF:

0.000255

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00100

AC:

1445

AN:

1444696

Hom.:

Cov.:

AF XY:

0.000986

AC XY:

708

AN XY:

717690

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

32628

American (AMR)

AF:

0.000991

AC:

AN:

42362

Ashkenazi Jewish (ASJ)

AF:

0.0000391

AC:

AN:

25596

East Asian (EAS)

AF:

0.00

AC:

AN:

38400

South Asian (SAS)

AF:

0.000380

AC:

AN:

84318

European-Finnish (FIN)

AF:

0.000254

AC:

AN:

51098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4710

European-Non Finnish (NFE)

AF:

0.00117

AC:

1294

AN:

1106004

Other (OTH)

AF:

0.000973

AC:

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<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:

0.000757

AC:

115

AN:

151956

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41426

American (AMR)

AF:

0.00222

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

67936

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000877

Hom.:

Bravo

AF:

0.000695

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 28 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.5

PromoterAI

0.064

Neutral

(source)

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over