14-53152762-TGCCGCC-TGCCGCCGCCGCCGCC

Variant names:

• chr14-53152762-T-TGCCGCCGCC
• rs55671452
• NM_001160148.2:c.328_336dupGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001160148.2(DDHD1):​c.328_336dupGGCGGCGGC​(p.Gly110_Gly112dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,576,608 control chromosomes in the GnomAD database, including 142 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (36 hom., cov: 0)
  • Exomes 𝑓: 0.0039 (106 hom.)
• Consequence: DDHD1 NM_001160148.2 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.972
• Publications: 7 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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001160148.2.
• BP6: Variant 14-53152762-T-TGCCGCCGCC is Benign according to our data. Variant chr14-53152762-T-TGCCGCCGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00964 (1452/150660) while in subpopulation AFR AF = 0.0122 (500/41052). AF 95% confidence interval is 0.0113. There are 36 homozygotes in GnomAd4. There are 881 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	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.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.328_336dupGGCGGCGGC	p.Gly110_Gly112dup	conservative_inframe_insertion	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes AF: 0.00964 AC: 1452 AN: 150552 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00851

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.00337

GnomAD2 exomes AF: 0.00886 AC: 1657 AN: 187002 AF XY: 0.00796

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00889

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00438

GnomAD4 exome AF: 0.00392 AC: 5587 AN: 1425948 Hom.: 106 Cov.: 111 AF XY: 0.00378 AC XY: 2670 AN XY: 707108

African (AFR) AF: 0.0124 AC: 409 AN: 32884

American (AMR) AF: 0.00135 AC: 53 AN: 39262

Ashkenazi Jewish (ASJ) AF: 0.00140 AC: 35 AN: 24980

East Asian (EAS) AF: 0.00736 AC: 283 AN: 38436

South Asian (SAS) AF: 0.00231 AC: 192 AN: 83114

European-Finnish (FIN) AF: 0.0637 AC: 3133 AN: 49182

Middle Eastern (MID) AF: 0.00196 AC: 9 AN: 4600

European-Non Finnish (NFE) AF: 0.00112 AC: 1225 AN: 1094604

Other (OTH) AF: 0.00421 AC: 248 AN: 58886

GnomAD4 genome AF: 0.00964 AC: 1452 AN: 150660 Hom.: 36 Cov.: 0 AF XY: 0.0120 AC XY: 881 AN XY: 73534

African (AFR) AF: 0.0122 AC: 500 AN: 41052

American (AMR) AF: 0.00118 AC: 18 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3456

East Asian (EAS) AF: 0.00854 AC: 42 AN: 4918

South Asian (SAS) AF: 0.00231 AC: 11 AN: 4768

European-Finnish (FIN) AF: 0.0690 AC: 720 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00224 AC: 151 AN: 67536

Other (OTH) AF: 0.00334 AC: 7 AN: 2098

Alfa AF: 0.00590 Hom.: 4554

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55671452; hg19: chr14-53619480;