14-53046760-AAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001160148.2(DDHD1):c.*6_*7del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 1,573,544 control chromosomes in the GnomAD database, including 558,594 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (52491 hom., cov: 0)
  • Exomes 𝑓: 0.84 (506103 hom.)
• Consequence: DDHD1 NM_001160148.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

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 -16 ACMG points.

• BP6: Variant 14-53046760-AAG-A is Benign according to our data. Variant chr14-53046760-AAG-A is described in ClinVar as [Benign]. Clinvar id is 1255133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-53046760-AAG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDHD1	NM_001160148.2	c.*6_*7del		3_prime_UTR_variant	13/13	ENST00000673822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDHD1	ENST00000673822.2	c.*6_*7del		3_prime_UTR_variant	13/13		NM_001160148.2	A2

Frequencies

GnomAD3 genomes AF: 0.840 AC: 125810 AN: 149804 Hom.: 52438 Cov.: 0

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.937

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.884

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.842

GnomAD3 exomes AF: 0.860 AC: 192694 AN: 224068 Hom.: 83269 AF XY: 0.859 AC XY: 104584 AN XY: 121750

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.904

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.977

Gnomad SAS exome AF: 0.880

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.847

GnomAD4 exome AF: 0.842 AC: 1199228 AN: 1423622 Hom.: 506103 AF XY: 0.844 AC XY: 597003 AN XY: 707736

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.899

Gnomad4 ASJ exome AF: 0.803

Gnomad4 EAS exome AF: 0.988

Gnomad4 SAS exome AF: 0.883

Gnomad4 FIN exome AF: 0.889

Gnomad4 NFE exome AF: 0.832

Gnomad4 OTH exome AF: 0.840

GnomAD4 genome AF: 0.840 AC: 125922 AN: 149922 Hom.: 52491 Cov.: 0 AF XY: 0.844 AC XY: 61816 AN XY: 73232

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.861

Gnomad4 ASJ AF: 0.806

Gnomad4 EAS AF: 0.980

Gnomad4 SAS AF: 0.885

Gnomad4 FIN AF: 0.891

Gnomad4 NFE AF: 0.835

Gnomad4 OTH AF: 0.842

Alfa AF: 0.836 Hom.: 6515

Bravo AF: 0.824

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2018

- -

Hereditary spastic paraplegia 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3037072; hg19: chr14-53513478;