14-53152963-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001160148.2(DDHD1):​c.136G>A​(p.Gly46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,585,200 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G46C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.015 (222 hom.)
• Consequence: DDHD1 NM_001160148.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020691454).
• BP6: Variant 14-53152963-C-T is Benign according to our data. Variant chr14-53152963-C-T is described in ClinVar as Benign. ClinVar VariationId is 238597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1891/152014) while in subpopulation NFE AF = 0.0177 (1201/67916). AF 95% confidence interval is 0.0169. There are 12 homozygotes in GnomAd4. There are 884 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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>A	p.Gly46Ser	missense	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.136G>A	p.Gly46Ser	missense	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.136G>A	p.Gly46Ser	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>A	p.Gly46Ser	missense	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.136G>A	p.Gly46Ser	missense	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.136G>A	p.Gly46Ser	missense	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1893 AN: 151900 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.0128 AC: 2409 AN: 188366 AF XY: 0.0127

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00575

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0149 AC: 21387 AN: 1433186 Hom.: 222 Cov.: 35 AF XY: 0.0146 AC XY: 10386 AN XY: 710698

African (AFR) AF: 0.00210 AC: 68 AN: 32400

American (AMR) AF: 0.00619 AC: 248 AN: 40052

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 754 AN: 25376

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38000

South Asian (SAS) AF: 0.00302 AC: 251 AN: 83040

European-Finnish (FIN) AF: 0.0208 AC: 1043 AN: 50150

Middle Eastern (MID) AF: 0.0148 AC: 66 AN: 4456

European-Non Finnish (NFE) AF: 0.0164 AC: 18085 AN: 1100514

Other (OTH) AF: 0.0147 AC: 871 AN: 59198

GnomAD4 genome AF: 0.0124 AC: 1891 AN: 152014 Hom.: 12 Cov.: 32 AF XY: 0.0119 AC XY: 884 AN XY: 74326

African (AFR) AF: 0.00323 AC: 134 AN: 41484

American (AMR) AF: 0.0102 AC: 156 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.0222 AC: 235 AN: 10590

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0177 AC: 1201 AN: 67916

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.0145 Hom.: 18

Bravo AF: 0.0106

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00423 AC: 18

ESP6500EA AF: 0.0170 AC: 138

ExAC AF: 0.0109 AC: 1254

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 28 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.31
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.036
Sift	Benign	0.34	T
Sift4G	Benign	0.42	T
Polyphen		0.0040	B
Vest4		0.032
MPC		0.44
ClinPred		0.0086	T
GERP RS		1.6
PromoterAI		0.034	Neutral
Varity_R		0.073
gMVP		0.34
Mutation Taster		=98/2	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;