Genetic Variant DDHD2:p.Ala417Val (chr8-38249709-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015214.3(DDHD2):c.1250C>T(p.Ala417Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A417D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DDHD2
NM_015214.3 missense, splice_region

Scores

Splicing: ADA: 0.001172

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

0 publications found

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]

DDHD2 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 54
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

DDHD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13902003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD2	NM_015214.3 link	c.1250C>T	p.Ala417Val	missense_variant, splice_region_variant	Exon 11 of 18	ENST00000397166.7	NP_056029.2	O94830-1B3KPM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD2	ENST00000397166.7 link	c.1250C>T	p.Ala417Val	missense_variant, splice_region_variant	Exon 11 of 18	2	NM_015214.3	ENSP00000380352.2		O94830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451700

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722716

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00

AC:

AN:

44134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104498

Other (OTH)

AF:

0.00

AC:

AN:

59938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.010

T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0094

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

.;T;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.

PhyloP100

1.3

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.23

N;N;N

REVEL

Benign

0.060

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.59

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.27

MutPred

0.52

Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;

MVP

0.41

MPC

0.15

ClinPred

0.36

GERP RS

4.6

PromoterAI

-0.0020

Neutral

(source)

Varity_R

0.023

gMVP

0.30

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.036

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over