14-53043392-A-AGTGTGT

Position:

• chr14-53043392-A-AGTGTGT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001160148.2(DDHD1):​c.*3375_*3376insACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.25 (2662 hom., cov: 0)
  • Exomes 𝑓: 0.045 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.*3375_*3376insACACAC		3_prime_UTR_variant	13/13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.*3375_*3376insACACAC		3_prime_UTR_variant	13/13		NM_001160148.2	ENSP00000500986	A2
DDHD1	ENST00000395606.5	c.*3375_*3376insACACAC		3_prime_UTR_variant	13/13	2		ENSP00000378970	A2

Frequencies

GnomAD3 genomes AF: 0.247 AC: 27615 AN: 111992 Hom.: 2660 Cov.: 0

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.0455 AC: 1 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.0714 AC XY: 1 AN XY: 14

Gnomad4 AFR exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.247 AC: 27633 AN: 112078 Hom.: 2662 Cov.: 0 AF XY: 0.250 AC XY: 13442 AN XY: 53788

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 24, 2017

- -

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: rs59747041; hg19: chr14-53510110;