14-53063185-T-G

Variant names:

• chr14-53063185-T-G
• rs138906273
• NM_001160148.2:c.1524A>C

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.1524A>C​(p.Gln508His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q508Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DDHD1 NM_001160148.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• 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=0.26019382).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160148.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	NM_001160148.2	MANE Select	c.1524A>C	p.Gln508His	missense	Exon 7 of 13	NP_001153620.1
	DDHD1	NM_001160147.2		c.1545A>C	p.Gln515His	missense	Exon 8 of 13	NP_001153619.1
	DDHD1	NM_030637.3		c.1524A>C	p.Gln508His	missense	Exon 7 of 12	NP_085140.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	ENST00000673822.2	MANE Select	c.1524A>C	p.Gln508His	missense	Exon 7 of 13	ENSP00000500986.2
	DDHD1	ENST00000357758.3	TSL:1	c.1524A>C	p.Gln508His	missense	Exon 7 of 12	ENSP00000350401.3
	DDHD1	ENST00000556027.5	TSL:1	n.2115A>C		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461366 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.36		Gain of catalytic residue at L510 (P = 0.0866)
MVP		0.29
MPC		0.98
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.38
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138906273; hg19: chr14-53529903;