14-53046806-G-A

Position:

chr14-53046806-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS1

The NM_001160148.2(DDHD1):c.2665C>T(p.His889Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,459,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

DDHD1
NM_001160148.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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:

DDHD1 (HGNC:):

DDHD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.078980625).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000295 (43/1459334) while in subpopulation MID AF= 0.00104 (6/5754). AF 95% confidence interval is 0.000454. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDHD1	NM_001160148.2 linkuse as main transcript	c.2665C>T	p.His889Tyr	missense_variant	13/13	ENST00000673822.2	NP_001153620.1	Q8NEL9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2 linkuse as main transcript	c.2665C>T	p.His889Tyr	missense_variant	13/13		NM_001160148.2	ENSP00000500986.2		Q8NEL9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000644

AC:

AN:

248618

Hom.:

AF XY:

0.0000892

AC XY:

AN XY:

134542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000396

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1459334

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000326

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000474

Hom.:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.2665C>T (p.H889Y) alteration is located in exon 13 (coding exon 13) of the DDHD1 gene. This alteration results from a C to T substitution at nucleotide position 2665, causing the histidine (H) at amino acid position 889 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

.;.;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.0028

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

.;.;N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.76

.;N;N;N

REVEL

Benign

0.078

Sift

Benign

0.074

.;T;T;T

Sift4G

Benign

0.98

T;T;T;T

Polyphen

0.93, 0.67

.;.;P;P

Vest4

0.32

MutPred

0.21

.;.;Gain of phosphorylation at H889 (P = 0.043);.;

MVP

0.043

MPC

0.59

ClinPred

0.061

GERP RS

5.9

Varity_R

0.037

gMVP

0.32

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