chr14-53152963-C-A

Variant names:

• chr14-53152963-C-A
• rs61985140
• NM_001160148.2:c.136G>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.136G>T​(p.Gly46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,433,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. G46S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.308
• Publications: 3 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-DT (HGNC:55441): (DDHD1 divergent transcript)

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=0.14022511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.136G>T	p.Gly46Cys	missense_variant	Exon 1 of 13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.136G>T	p.Gly46Cys	missense_variant	Exon 1 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 3 AN: 188366 AF XY: 0.00000967

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000705

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1433194 Hom.: 0 Cov.: 35 AF XY: 0.00000422 AC XY: 3 AN XY: 710704

African (AFR) AF: 0.00 AC: 0 AN: 32400

American (AMR) AF: 0.0000749 AC: 3 AN: 40052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 38000

South Asian (SAS) AF: 0.00 AC: 0 AN: 83042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4456

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100518

Other (OTH) AF: 0.0000169 AC: 1 AN: 59200

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 18

Bravo AF: 0.00000378

ExAC AF: 0.00000870 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 28 Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 46 of the DDHD1 protein (p.Gly46Cys). This variant is present in population databases (rs61985140, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DDHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1461076). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0092	.;.;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	.;L;L;L
PhyloP100		0.31
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.85	.;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.040	.;D;D;D
Sift4G	Benign	0.064	T;T;T;T
Polyphen		0.94, 0.91	.;.;P;P
Vest4		0.31
MVP		0.068
MPC		0.99
ClinPred		0.19	T
GERP RS		1.6
PromoterAI		0.033	Neutral
Varity_R		0.18
gMVP		0.49
Mutation Taster		=90/10	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

dbSNP: rs61985140; hg19: chr14-53619681;