rs1475369039

Variant names:

• chr8-38234542-TA-T
• rs1475369039
• NM_015214.3:c.371delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015214.3(DDHD2):​c.371delA​(p.Lys124SerfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000226 in 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: DDHD2 NM_015214.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.62
• Publications: 0 publications found

Genes affected

DDHD2 (HGNC:29106): (DDHD domain containing 2) This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

DDHD2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 54

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38234542-TA-T is Pathogenic according to our data. Variant chr8-38234542-TA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 473074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	NM_015214.3	MANE Select	c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	NP_001349840.1	O94830-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD2	ENST00000397166.7	TSL:2 MANE Select	c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.371delA	p.Lys124SerfsTer13	frameshift	Exon 3 of 18	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249676 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1460270 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726464

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 85868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111704

Other (OTH) AF: 0.0000332 AC: 2 AN: 60306

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary spastic paraplegia 54 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1475369039; hg19: chr8-38092060;