14-53046611-CTTTT-CTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The ENST00000556027.5(DDHD1):​n.3366delA 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 0.0103 in 404,286 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: DDHD1 ENST00000556027.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0152) population. However there is too low homozygotes in high coverage region: (expected more than 10, got 0).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000388 (50/128904) while in subpopulation EAS AF = 0.000785 (4/5098). AF 95% confidence interval is 0.000346. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 50 AN: 128840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.000208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000478

Gnomad OTH AF: 0.000553

GnomAD4 exome AF: 0.0149 AC: 4113 AN: 275382 Hom.: 0 Cov.: 5 AF XY: 0.0154 AC XY: 2159 AN XY: 140294

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

African (AFR) AF: 0.0138 AC: 78 AN: 5656

American (AMR) AF: 0.0175 AC: 118 AN: 6760

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 106 AN: 7880

East Asian (EAS) AF: 0.0133 AC: 257 AN: 19252

South Asian (SAS) AF: 0.0168 AC: 157 AN: 9356

European-Finnish (FIN) AF: 0.0111 AC: 333 AN: 29962

Middle Eastern (MID) AF: 0.0168 AC: 20 AN: 1188

European-Non Finnish (NFE) AF: 0.0156 AC: 2813 AN: 179848

Other (OTH) AF: 0.0149 AC: 231 AN: 15480

⚠️ 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: 0.000388 AC: 50 AN: 128904 Hom.: 0 Cov.: 32 AF XY: 0.000507 AC XY: 32 AN XY: 63094

African (AFR) AF: 0.000358 AC: 9 AN: 25168

American (AMR) AF: 0.000147 AC: 2 AN: 13642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3188

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

South Asian (SAS) AF: 0.000218 AC: 1 AN: 4594

European-Finnish (FIN) AF: 0.000208 AC: 2 AN: 9634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000478 AC: 31 AN: 64800

Other (OTH) AF: 0.000547 AC: 1 AN: 1828

Alfa AF: 0.0000542 Hom.: 0

ClinVar

Not reported in ClinVar

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: COSV60361283; COSMIC: COSV60361283;