14-53152762-TGCCGCC-TGCCGCCGCC

Variant names:

• chr14-53152762-T-TGCC
• rs55671452
• NM_001160148.2:c.334_336dupGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_001160148.2(DDHD1):​c.334_336dupGGC​(p.Gly112dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,567,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000099 (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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001160148.2. Strenght limited to Supporting due to length of the change: 1aa.

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.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.334_336dupGGC	p.Gly112dup	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.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes AF: 0.0000598 AC: 9 AN: 150536 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000385 AC: 72 AN: 187002 AF XY: 0.000435

Gnomad AFR exome AF: 0.0000960

Gnomad AMR exome AF: 0.000257

Gnomad ASJ exome AF: 0.000377

Gnomad EAS exome AF: 0.000353

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000626

GnomAD4 exome AF: 0.0000995 AC: 141 AN: 1417320 Hom.: 0 Cov.: 111 AF XY: 0.0000996 AC XY: 70 AN XY: 702832

African (AFR) AF: 0.0000610 AC: 2 AN: 32776

American (AMR) AF: 0.000258 AC: 10 AN: 38790

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 3 AN: 24780

East Asian (EAS) AF: 0.000183 AC: 7 AN: 38208

South Asian (SAS) AF: 0.0000971 AC: 8 AN: 82414

European-Finnish (FIN) AF: 0.000102 AC: 5 AN: 48940

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4570

European-Non Finnish (NFE) AF: 0.0000937 AC: 102 AN: 1088264

Other (OTH) AF: 0.0000512 AC: 3 AN: 58578

GnomAD4 genome AF: 0.0000597 AC: 9 AN: 150644 Hom.: 0 Cov.: 0 AF XY: 0.0000408 AC XY: 3 AN XY: 73520

African (AFR) AF: 0.0000244 AC: 1 AN: 41046

American (AMR) AF: 0.0000657 AC: 1 AN: 15210

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

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

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67526

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

Alfa AF: 0.0101 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;