14-53152762-TGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr14-53152762-T-TGCCGCCGCCGCCGCCGCC
• rs55671452
• NM_001160148.2:c.336_337insGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001160148.2(DDHD1):​c.336_337insGGCGGCGGCGGCGGCGGC​(p.Gly112_Ser113insGlyGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,576,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.972
• Publications: 7 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001160148.2.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	NM_001160148.2	MANE Select	c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 12	NP_085140.2	Q8NEL9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	ENST00000673822.2	MANE Select	c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.336_337insGGCGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes AF: 0.0000465 AC: 7 AN: 150570 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 60 AN: 1425976 Hom.: 0 Cov.: 111 AF XY: 0.0000438 AC XY: 31 AN XY: 707124

African (AFR) AF: 0.0000304 AC: 1 AN: 32884

American (AMR) AF: 0.000153 AC: 6 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24980

East Asian (EAS) AF: 0.00 AC: 0 AN: 38438

South Asian (SAS) AF: 0.000229 AC: 19 AN: 83112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.0000210 AC: 23 AN: 1094614

Other (OTH) AF: 0.000187 AC: 11 AN: 58888

GnomAD4 genome AF: 0.0000465 AC: 7 AN: 150678 Hom.: 0 Cov.: 0 AF XY: 0.0000408 AC XY: 3 AN XY: 73548

African (AFR) AF: 0.000122 AC: 5 AN: 41052

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67538

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.0000703 Hom.: 4554

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs55671452; hg19: chr14-53619480;