14-53046775-G-A

Variant names:

• chr14-53046775-G-A
• NM_001160148.2:c.2696C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001160148.2(DDHD1):​c.2696C>T​(p.Pro899Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P899A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.11
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 28

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

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=0.11338335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.2696C>T	p.Pro899Leu	missense_variant	Exon 13 of 13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.2696C>T	p.Pro899Leu	missense_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447510 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 719962

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

African (AFR) AF: 0.00 AC: 0 AN: 32718

American (AMR) AF: 0.00 AC: 0 AN: 42828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39104

South Asian (SAS) AF: 0.00 AC: 0 AN: 83720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104744

Other (OTH) AF: 0.00 AC: 0 AN: 59840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2696C>T (p.P899L) 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 2696, causing the proline (P) at amino acid position 899 to be replaced by a leucine (L). 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	0.094
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0089	.;.;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	.;.;L;.
PhyloP100		5.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.95	.;N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.10, 0.14	.;.;B;B
Vest4		0.13
MutPred		0.23		.;.;Loss of relative solvent accessibility (P = 0.0404);.;
MVP		0.082
MPC		0.52
ClinPred		0.81	D
GERP RS		5.9
Varity_R		0.087
gMVP		0.65
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

hg19: chr14-53513493;