14-53046806-G-A

Variant names:

• chr14-53046806-G-A
• rs760306971
• NM_001160148.2:c.2665C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H889H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.078980625).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.2665C>T	p.His889Tyr	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.2665C>T	p.His889Tyr	missense_variant	Exon 13 of 13		NM_001160148.2	ENSP00000500986.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000644 AC: 16 AN: 248618 AF XY: 0.0000892

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1459334 Hom.: 0 Cov.: 32 AF XY: 0.0000427 AC XY: 31 AN XY: 726004

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.000326 AC: 28 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5754

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110608

Other (OTH) AF: 0.0000166 AC: 1 AN: 60300

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000474 Hom.: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.079	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	.;.;N;.
PhyloP100		3.5
PrimateAI	Benign	0.39	T
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	T
GERP RS		5.9
Varity_R		0.037
gMVP		0.32
Mutation Taster		=81/19	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: rs760306971; hg19: chr14-53513524;