rs61985140

Variant names:

• chr14-53152963-C-A
• rs61985140
• NM_001160148.2:c.136G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-53152963-C-A
• chr14-53152963-C-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).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	NM_001160148.2	MANE Select	c.136G>T	p.Gly46Cys	missense	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.136G>T	p.Gly46Cys	missense	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.136G>T	p.Gly46Cys	missense	Exon 1 of 12	NP_085140.2	Q8NEL9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDHD1	ENST00000673822.2	MANE Select	c.136G>T	p.Gly46Cys	missense	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.136G>T	p.Gly46Cys	missense	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.136G>T	p.Gly46Cys	missense	Exon 1 of 15	ENSP00000577235.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 28 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.31
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.089
Sift	Benign	0.040	D
Sift4G	Benign	0.064	T
Polyphen		0.94	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;