8-38247714-A-G

Position:

chr8-38247714-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015214.3(DDHD2):c.1127A>G(p.Asp376Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,489,866 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0043 ( 10 hom. )

Consequence

DDHD2
NM_015214.3 missense, splice_region

Scores

Splicing: ADA: 0.00008901

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.606

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024392903).

BP6

Variant 8-38247714-A-G is Benign according to our data. Variant chr8-38247714-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210838.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 = 0.0029 (442/152312) while in subpopulation NFE AF= 0.00494 (336/68026). AF 95% confidence interval is 0.0045. There are 2 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD2	NM_015214.3 linkuse as main transcript	c.1127A>G	p.Asp376Gly	missense_variant, splice_region_variant	10/18	ENST00000397166.7	NP_056029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDHD2	ENST00000397166.7 linkuse as main transcript	c.1127A>G	p.Asp376Gly	missense_variant, splice_region_variant	10/18	2	NM_015214.3	ENSP00000380352	P1	O94830-1

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

442

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00293

AC:

550

AN:

187908

Hom.:

AF XY:

0.00297

AC XY:

308

AN XY:

103790

show subpopulations

Gnomad AFR exome

AF:

0.000605

Gnomad AMR exome

AF:

0.00178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00254

GnomAD4 exome

AF:

0.00429

AC:

5740

AN:

1337554

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

2810

AN XY:

665698

show subpopulations

Gnomad4 AFR exome

AF:

0.000677

Gnomad4 AMR exome

AF:

0.00220

Gnomad4 ASJ exome

AF:

0.0000896

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000141

Gnomad4 FIN exome

AF:

0.00322

Gnomad4 NFE exome

AF:

0.00503

Gnomad4 OTH exome

AF:

0.00450

GnomAD4 genome

AF:

0.00290

AC:

442

AN:

152312

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00478

AC:

ExAC

AF:

0.00272

AC:

330

Asia WGS

AF:

0.000579

AC:

AN:

3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 54

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DDHD2: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2016

- -

DDHD2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.0096

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.55

.;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.44

N;N

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.066

Sift

Benign

0.27

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;B

Vest4

0.082

MVP

0.040

MPC

0.19

ClinPred

0.0029

GERP RS

-6.1

Varity_R

0.038

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000089

dbscSNV1_RF

Benign

0.054

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over