chr14-53046752-T-C

Variant names:

• chr14-53046752-T-C
• rs112663760
• ENST00000556027.5:n.3226A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000556027.5(DDHD1):​n.3226A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,436,872 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.022 (10 hom., cov: 30)
  • Exomes 𝑓: 0.00060 (11 hom.)
• Consequence: DDHD1 ENST00000556027.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.414
• Publications: 0 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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 28

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.*16A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.*16A>G		3_prime_UTR_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 907 AN: 41842 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.0793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00650

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00194

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000928

Gnomad OTH AF: 0.0137

GnomAD2 exomes AF: 0.00386 AC: 332 AN: 85992 AF XY: 0.00255

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000607

GnomAD4 exome AF: 0.000601 AC: 838 AN: 1395030 Hom.: 11 Cov.: 25 AF XY: 0.000489 AC XY: 339 AN XY: 692598

African (AFR) AF: 0.0233 AC: 705 AN: 30288

American (AMR) AF: 0.000806 AC: 29 AN: 36002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24220

East Asian (EAS) AF: 0.00 AC: 0 AN: 37368

South Asian (SAS) AF: 0.0000930 AC: 7 AN: 75272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51878

Middle Eastern (MID) AF: 0.000543 AC: 3 AN: 5520

European-Non Finnish (NFE) AF: 0.0000186 AC: 20 AN: 1076952

Other (OTH) AF: 0.00129 AC: 74 AN: 57530

GnomAD4 genome AF: 0.0217 AC: 909 AN: 41842 Hom.: 10 Cov.: 30 AF XY: 0.0216 AC XY: 430 AN XY: 19920

African (AFR) AF: 0.0793 AC: 873 AN: 11006

American (AMR) AF: 0.00650 AC: 24 AN: 3692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1272

East Asian (EAS) AF: 0.00 AC: 0 AN: 310

South Asian (SAS) AF: 0.00196 AC: 2 AN: 1020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 98

European-Non Finnish (NFE) AF: 0.0000928 AC: 2 AN: 21544

Other (OTH) AF: 0.0135 AC: 8 AN: 592

Alfa AF: 0.000903 Hom.: 0

Bravo AF: 0.00666

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 02, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs112663760; hg19: chr14-53513470;