14-53046759-CAA-C

Variant names:

• chr14-53046759-CAA-C
• rs33960665
• ENST00000556027.5:n.3217_3218delTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001160148.2(DDHD1):​c.*7_*8delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,214,006 control chromosomes in the GnomAD database, including 491 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (251 hom., cov: 0)
  • Exomes 𝑓: 0.0039 (240 hom.)
• Consequence: DDHD1 NM_001160148.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.414
• Publications: 2 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 14-53046759-CAA-C is Benign according to our data. Variant chr14-53046759-CAA-C is described in ClinVar as [Benign]. Clinvar id is 1182240.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.*7_*8delTT		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.*7_*8delTT		3_prime_UTR_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 4770 AN: 45280 Hom.: 251 Cov.: 0

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.00210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0490

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0757

GnomAD2 exomes AF: 0.0340 AC: 1775 AN: 52278 AF XY: 0.0232

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.0390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.00395 AC: 4613 AN: 1168714 Hom.: 240 AF XY: 0.00358 AC XY: 2083 AN XY: 581178

African (AFR) AF: 0.128 AC: 3390 AN: 26482

American (AMR) AF: 0.0103 AC: 291 AN: 28224

Ashkenazi Jewish (ASJ) AF: 0.0000477 AC: 1 AN: 20962

East Asian (EAS) AF: 0.000145 AC: 5 AN: 34538

South Asian (SAS) AF: 0.000301 AC: 18 AN: 59762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48746

Middle Eastern (MID) AF: 0.0100 AC: 48 AN: 4800

European-Non Finnish (NFE) AF: 0.000485 AC: 435 AN: 896178

Other (OTH) AF: 0.00867 AC: 425 AN: 49022

GnomAD4 genome AF: 0.105 AC: 4772 AN: 45292 Hom.: 251 Cov.: 0 AF XY: 0.105 AC XY: 2245 AN XY: 21456

African (AFR) AF: 0.274 AC: 4417 AN: 16122

American (AMR) AF: 0.0702 AC: 268 AN: 3820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1190

East Asian (EAS) AF: 0.0153 AC: 3 AN: 196

South Asian (SAS) AF: 0.00212 AC: 2 AN: 942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1968

Middle Eastern (MID) AF: 0.0532 AC: 5 AN: 94

European-Non Finnish (NFE) AF: 0.00153 AC: 31 AN: 20238

Other (OTH) AF: 0.0747 AC: 46 AN: 616

Alfa AF: 0.0239 Hom.: 9

Bravo AF: 0.0364

Asia WGS AF: 0.0100 AC: 19 AN: 1804

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 21, 2017

GeneDx

Significance: 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		0.41
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: rs33960665; hg19: chr14-53513477;