14-53046611-C-CT

Variant names:

• chr14-53046611-C-CT
• rs113463836
• ENST00000556027.5:n.3366dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001160148.2(DDHD1):​c.*156dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 413,008 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.71
• 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 -10 ACMG points.

• BP6: Variant 14-53046611-C-CT is Benign according to our data. Variant chr14-53046611-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 1218404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00468 (604/128970) while in subpopulation AFR AF = 0.018 (454/25170). AF 95% confidence interval is 0.0167. There are 2 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.*156dupA		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.*156dupA		3_prime_UTR_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 602 AN: 128906 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.000627

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000434

Gnomad FIN AF: 0.000104

Gnomad MID AF: 0.00350

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00442

GnomAD4 exome AF: 0.00550 AC: 1561 AN: 284038 Hom.: 0 Cov.: 5 AF XY: 0.00567 AC XY: 822 AN XY: 144898

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0188 AC: 109 AN: 5804

American (AMR) AF: 0.00903 AC: 63 AN: 6974

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 39 AN: 8216

East Asian (EAS) AF: 0.00361 AC: 72 AN: 19952

South Asian (SAS) AF: 0.00773 AC: 74 AN: 9568

European-Finnish (FIN) AF: 0.00380 AC: 117 AN: 30784

Middle Eastern (MID) AF: 0.00488 AC: 6 AN: 1230

European-Non Finnish (NFE) AF: 0.00546 AC: 1013 AN: 185522

Other (OTH) AF: 0.00425 AC: 68 AN: 15988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00468 AC: 604 AN: 128970 Hom.: 2 Cov.: 32 AF XY: 0.00488 AC XY: 308 AN XY: 63134

African (AFR) AF: 0.0180 AC: 454 AN: 25170

American (AMR) AF: 0.00660 AC: 90 AN: 13644

Ashkenazi Jewish (ASJ) AF: 0.000627 AC: 2 AN: 3188

East Asian (EAS) AF: 0.000785 AC: 4 AN: 5098

South Asian (SAS) AF: 0.000435 AC: 2 AN: 4596

European-Finnish (FIN) AF: 0.000104 AC: 1 AN: 9654

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.000648 AC: 42 AN: 64840

Other (OTH) AF: 0.00438 AC: 8 AN: 1828

Alfa AF: 0.0000542 Hom.: 0

Bravo AF: 0.00453

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
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: rs113463836; hg19: chr14-53513329; COSMIC: COSV100079778; COSMIC: COSV100079778;