14-53152646-C-T

Position:

• chr14-53152646-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001160148.2(DDHD1):​c.453G>A​(p.Pro151Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,613,068 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (210 hom.)
• Consequence: DDHD1 NM_001160148.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-53152646-C-T is Benign according to our data. Variant chr14-53152646-C-T is described in ClinVar as [Benign]. Clinvar id is 380446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.453G>A	p.Pro151Pro	synonymous_variant	1/13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.453G>A	p.Pro151Pro	synonymous_variant	1/13		NM_001160148.2	ENSP00000500986.2
DDHD1	ENST00000357758.3	c.453G>A	p.Pro151Pro	synonymous_variant	1/12	1		ENSP00000350401.3
DDHD1	ENST00000395606.5	c.453G>A	p.Pro151Pro	synonymous_variant	1/13	2		ENSP00000378970.1
DDHD1	ENST00000673930.1	c.-31G>A		upstream_gene_variant				ENSP00000501087.1

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 984 AN: 152190 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0144 AC: 3553 AN: 247212 Hom.: 175 AF XY: 0.0105 AC XY: 1411 AN XY: 134752

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00584

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000631

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00320 AC: 4673 AN: 1460760 Hom.: 210 Cov.: 31 AF XY: 0.00268 AC XY: 1944 AN XY: 726726

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00386

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152308 Hom.: 41 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74462

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.0560

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00504

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.0122

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 19, 2021

- -

Hereditary spastic paraplegia 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.9
DANN	Benign	0.95

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: rs141323589; hg19: chr14-53619364;