chr14-53152762-T-TGCC

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001160148.2. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13		NM_001160148.2	ENSP00000500986.2
DDHD1	ENST00000357758.3	c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 12	1		ENSP00000350401.3
DDHD1	ENST00000395606.5	c.334_336dupGGC	p.Gly112dup	conservative_inframe_insertion	Exon 1 of 13	2		ENSP00000378970.1
DDHD1	ENST00000673930.1	c.-150_-148dupGGC		upstream_gene_variant				ENSP00000501087.1

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

GnomAD3 exomes AF: 0.000385 AC: 72 AN: 187002 Hom.: 0 AF XY: 0.000435 AC XY: 45 AN XY: 103428

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 SAS exome AF: 0.000617

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

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.000258

Gnomad4 ASJ exome AF: 0.000121

Gnomad4 EAS exome AF: 0.000183

Gnomad4 SAS exome AF: 0.0000971

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.0000937

Gnomad4 OTH exome AF: 0.0000512

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

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000104

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 28 Uncertain:1

Aug 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.334_336dup, results in the insertion of 1 amino acid(s) of the DDHD1 protein (p.Gly112dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DDHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 965736). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55671452; hg19: chr14-53619480;