14-53046760-AAG-A

Variant names:

• chr14-53046760-AAG-A
• rs3037072
• ENST00000556027.5:n.3216_3217delCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001160148.2(DDHD1):​c.*6_*7delCT 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
• 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 -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.
• 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 rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.*6_*7delCT		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.*6_*7delCT		3_prime_UTR_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

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

GnomAD2 exomes AF: 0.860 AC: 192694 AN: 224068 AF XY: 0.859

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 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

African (AFR) AF: 0.808 AC: 24472 AN: 30302

American (AMR) AF: 0.899 AC: 35958 AN: 39996

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 20173 AN: 25130

East Asian (EAS) AF: 0.988 AC: 37940 AN: 38410

South Asian (SAS) AF: 0.883 AC: 70452 AN: 79786

European-Finnish (FIN) AF: 0.889 AC: 46776 AN: 52598

Middle Eastern (MID) AF: 0.830 AC: 4664 AN: 5618

European-Non Finnish (NFE) AF: 0.832 AC: 909496 AN: 1093098

Other (OTH) AF: 0.840 AC: 49297 AN: 58684

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

African (AFR) AF: 0.803 AC: 31950 AN: 39774

American (AMR) AF: 0.861 AC: 13039 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2793 AN: 3464

East Asian (EAS) AF: 0.980 AC: 5057 AN: 5158

South Asian (SAS) AF: 0.885 AC: 4251 AN: 4804

European-Finnish (FIN) AF: 0.891 AC: 9274 AN: 10406

Middle Eastern (MID) AF: 0.823 AC: 237 AN: 288

European-Non Finnish (NFE) AF: 0.835 AC: 56714 AN: 67886

Other (OTH) AF: 0.842 AC: 1754 AN: 2084

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

Jun 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 28 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3037072; hg19: chr14-53513478; COSMIC: COSV60356823; COSMIC: COSV60356823;