rs759522859

Variant names:

• chr8-38234388-TGAAAG-T
• rs759522859
• NM_015214.3:c.221-1_224delGGAAA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1 BS1_Supporting

The NM_015214.3(DDHD2):​c.221-1_224delGGAAA​(p.Gly74fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.000027 in 1,556,178 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (1 hom.)
• Consequence: DDHD2 NM_015214.3 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.11
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000112 (17/152196) while in subpopulation AFR AF = 0.000362 (15/41444). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.221-1_224delGGAAA	p.Gly74fs	frameshift splice_acceptor splice_region intron	Exon 3 of 18	NP_056029.2	O94830-1
	DDHD2	NM_001164232.2		c.221-1_224delGGAAA	p.Gly74fs	frameshift splice_acceptor splice_region intron	Exon 3 of 18	NP_001157704.1	O94830-1
	DDHD2	NM_001362911.2		c.221-1_224delGGAAA	p.Gly74fs	frameshift splice_acceptor splice_region intron	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.221-5_221-1delGAAAG		splice_acceptor splice_region intron	N/A	ENSP00000380352.2	O94830-1
	DDHD2	ENST00000853787.1		c.221-5_221-1delGAAAG		splice_acceptor splice_region intron	N/A	ENSP00000523846.1
	DDHD2	ENST00000520272.6	TSL:2	c.221-5_221-1delGAAAG		splice_acceptor splice_region intron	N/A	ENSP00000429932.2	O94830-1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000727 AC: 15 AN: 206436 AF XY: 0.0000265

Gnomad AFR exome AF: 0.000553

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000295

Gnomad OTH exome AF: 0.000211

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1403982 Hom.: 1 AF XY: 0.0000172 AC XY: 12 AN XY: 696394

African (AFR) AF: 0.000328 AC: 10 AN: 30516

American (AMR) AF: 0.0000336 AC: 1 AN: 29758

Ashkenazi Jewish (ASJ) AF: 0.0000823 AC: 2 AN: 24304

East Asian (EAS) AF: 0.00 AC: 0 AN: 37200

South Asian (SAS) AF: 0.0000262 AC: 2 AN: 76368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5596

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1089734

Other (OTH) AF: 0.0000865 AC: 5 AN: 57794

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

African (AFR) AF: 0.000362 AC: 15 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 54 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=91/9	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759522859; hg19: chr8-38091906;