14-53152762-TGCCGCC-TGCCGCCGCCGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4BP6_ModerateBS1

The NM_001160148.2(DDHD1):c.336_337insGGCGGCGGCGGCGGC(p.Gly112_Ser113insGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00025 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

DDHD1
NM_001160148.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.972

Publications

7 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: Likely_benign. The variant received -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001160148.2.

BP6

Variant 14-53152762-T-TGCCGCCGCCGCCGCC is Benign according to our data. Variant chr14-53152762-T-TGCCGCCGCCGCCGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 464311.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000929 (140/150678) while in subpopulation AFR AF = 0.003 (123/41052). AF 95% confidence interval is 0.00257. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
DDHD1	NM_001160147.2		c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
DDHD1	NM_030637.3		c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	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.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
DDHD1	ENST00000357758.3	TSL:1	c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
DDHD1	ENST00000907176.1		c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes

AF:

0.000930

AC:

140

AN:

150570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.000628

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000299

AC:

AN:

187002

AF XY:

0.000261

show subpopulations

Gnomad AFR exome

AF:

0.00278

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000357

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.000417

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000255

AC:

363

AN:

1425976

Hom.:

Cov.:

111

AF XY:

0.000243

AC XY:

172

AN XY:

707122

show subpopulations

African (AFR)

AF:

0.00341

AC:

112

AN:

32882

American (AMR)

AF:

0.000153

AC:

AN:

39264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24980

East Asian (EAS)

AF:

0.000182

AC:

AN:

38440

South Asian (SAS)

AF:

0.000144

AC:

AN:

83114

European-Finnish (FIN)

AF:

0.000325

AC:

AN:

49196

Middle Eastern (MID)

AF:

0.000652

AC:

AN:

4600

European-Non Finnish (NFE)

AF:

0.000173

AC:

189

AN:

1094614

Other (OTH)

AF:

0.000306

AC:

AN:

58886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000929

AC:

140

AN:

150678

Hom.:

Cov.:

AF XY:

0.000897

AC XY:

AN XY:

73548

show subpopulations

African (AFR)

AF:

0.00300

AC:

123

AN:

41052

American (AMR)

AF:

0.000131

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.000203

AC:

AN:

4918

South Asian (SAS)

AF:

0.000629

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10444

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67538

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000422

Hom.:

4554

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 28 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.97

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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