8-38234388-TGAAAG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BS1_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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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;
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DDHD2NM_015214.3 linkc.221-1_224delGGAAA p.Gly74fs frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant Exon 3 of 18 ENST00000397166.7 NP_056029.2 O94830-1B3KPM6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DDHD2ENST00000397166.7 linkc.221-5_221-1delGAAAG splice_acceptor_variant, splice_region_variant, intron_variant Intron 2 of 17 2 NM_015214.3 ENSP00000380352.2 O94830-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.0000727
AC:
15
AN:
206436
Hom.:
1
AF XY:
0.0000265
AC XY:
3
AN XY:
113016
show subpopulations
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 SAS exome
AF:
0.0000903
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000328
Gnomad4 AMR exome
AF:
0.0000336
Gnomad4 ASJ exome
AF:
0.0000823
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000262
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000367
Gnomad4 OTH exome
AF:
0.0000865
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000162

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 54 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 02, 2018This sequence change affects an acceptor splice site in intron 3 of the DDHD2 gene. It is expected to disrupt RNA splicing and may result in a disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with DDHD2-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759522859; hg19: chr8-38091906; API