rs180742508

Variant names:

• chr14-53072587-T-A
• rs180742508
• NM_001160148.2:c.1503+10A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-53072587-T-A
• chr14-53072587-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001160148.2(DDHD1):​c.1503+10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,453,538 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: DDHD1 NM_001160148.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 14-53072587-T-A is Benign according to our data. Variant chr14-53072587-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00179 (273/152178) while in subpopulation NFE AF = 0.00314 (213/67926). AF 95% confidence interval is 0.00279. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160148.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	NM_001160148.2	MANE Select	c.1503+10A>T		intron	N/A	NP_001153620.1
	DDHD1	NM_001160147.2		c.1524+10A>T		intron	N/A	NP_001153619.1
	DDHD1	NM_030637.3		c.1503+10A>T		intron	N/A	NP_085140.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	ENST00000673822.2	MANE Select	c.1503+10A>T		intron	N/A	ENSP00000500986.2
	DDHD1	ENST00000357758.3	TSL:1	c.1503+10A>T		intron	N/A	ENSP00000350401.3
	DDHD1	ENST00000556027.5	TSL:1	n.2094+10A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00280 AC: 609 AN: 217404 AF XY: 0.00281

Gnomad AFR exome AF: 0.000483

Gnomad AMR exome AF: 0.000282

Gnomad ASJ exome AF: 0.00204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00511

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00289 AC: 3761 AN: 1301360 Hom.: 4 Cov.: 18 AF XY: 0.00290 AC XY: 1863 AN XY: 643400

African (AFR) AF: 0.000370 AC: 11 AN: 29760

American (AMR) AF: 0.000257 AC: 9 AN: 35022

Ashkenazi Jewish (ASJ) AF: 0.00219 AC: 49 AN: 22330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37574

South Asian (SAS) AF: 0.00 AC: 0 AN: 63210

European-Finnish (FIN) AF: 0.00286 AC: 141 AN: 49246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 0.00341 AC: 3432 AN: 1005588

Other (OTH) AF: 0.00223 AC: 119 AN: 53440

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74398

African (AFR) AF: 0.000433 AC: 18 AN: 41572

American (AMR) AF: 0.000328 AC: 5 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00314 AC: 213 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 28 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.32
DANN	Benign	0.60
PhyloP100		-1.1
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: rs180742508; hg19: chr14-53539305;