14-53152963-C-T

Position:

chr14-53152963-C-T

Variant summary

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

The NM_001160148.2(DDHD1):c.136G>A(p.Gly46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,585,200 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 12 hom., cov: 32)

Exomes 𝑓: 0.015 ( 222 hom. )

Consequence

DDHD1
NM_001160148.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.308

Variant links:

Genes affected

DDHD1 (HGNC:19714): (DDHD domain containing 1) This gene is a member of the intracellular phospholipase A1 gene family. The protein encoded by this gene preferentially hydrolyzes phosphatidic acid. It is a cytosolic protein with some mitochondrial localization, and is thought to be involved in the regulation of mitochondrial dynamics. Overexpression of this gene causes fragmentation of the tubular structures in mitochondria, while depletion of the gene results in mitochondrial tubule elongation. Deletion of this gene in male mice caused fertility defects, resulting from disruption in the organization of the mitochondria during spermiogenesis. In humans, mutations in this gene have been associated with hereditary spastic paraplegia (HSP), also known as Strumpell-Lorrain disease, or, familial spastic paraparesis (FSP). This inherited disorder is characterized by progressive weakness and spasticity of the legs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

DDHD1 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=0.0020691454).

BP6

Variant 14-53152963-C-T is Benign according to our data. Variant chr14-53152963-C-T is described in ClinVar as [Benign]. Clinvar id is 238597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-53152963-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1891/152014) while in subpopulation NFE AF= 0.0177 (1201/67916). AF 95% confidence interval is 0.0169. There are 12 homozygotes in gnomad4. There are 884 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD1	NM_001160148.2 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/13	ENST00000673822.2	NP_001153620.1	Q8NEL9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DDHD1	ENST00000673822.2 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/13		NM_001160148.2	ENSP00000500986.2	Q8NEL9-1
DDHD1	ENST00000357758.3 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/12	1		ENSP00000350401.3	Q8NEL9-2
DDHD1	ENST00000395606.5 linkuse as main transcript	c.136G>A	p.Gly46Ser	missense_variant	1/13	2		ENSP00000378970.1	Q8NEL9-4

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1893

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0222

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.00767

GnomAD3 exomes

AF:

0.0128

AC:

2409

AN:

188366

Hom.:

AF XY:

0.0127

AC XY:

1309

AN XY:

103406

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.0294

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00290

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0149

AC:

21387

AN:

1433186

Hom.:

222

Cov.:

AF XY:

0.0146

AC XY:

10386

AN XY:

710698

show subpopulations

Gnomad4 AFR exome

AF:

0.00210

Gnomad4 AMR exome

AF:

0.00619

Gnomad4 ASJ exome

AF:

0.0297

Gnomad4 EAS exome

AF:

0.0000263

Gnomad4 SAS exome

AF:

0.00302

Gnomad4 FIN exome

AF:

0.0208

Gnomad4 NFE exome

AF:

0.0164

Gnomad4 OTH exome

AF:

0.0147

GnomAD4 genome

AF:

0.0124

AC:

1891

AN:

152014

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

884

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00323

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0222

Gnomad4 NFE

AF:

0.0177

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00423

AC:

ESP6500EA

AF:

0.0170

AC:

138

ExAC

AF:

0.0109

AC:

1254

Asia WGS

AF:

0.00202

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 25, 2020

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hereditary spastic paraplegia 28

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0060

.;.;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.060

.;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.34

.;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.0040, 0.0030

.;.;B;B

Vest4

0.032

MPC

0.44

ClinPred

0.0086

GERP RS

1.6

Varity_R

0.073

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

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