14-53152762-TGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant names:

• chr14-53152762-T-TGCCGCCGCCGCC
• rs55671452
• NM_001160148.2:c.325_336dupGGCGGCGGCGGC

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.325_336dupGGCGGCGGCGGC​(p.Gly112_Ser113insGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,576,654 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: DDHD1 NM_001160148.2 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-TGCCGCCGCCGCC is Benign according to our data. Variant chr14-53152762-T-TGCCGCCGCCGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695810.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 = 0.000923 (139/150676) while in subpopulation NFE AF = 0.00123 (83/67538). AF 95% confidence interval is 0.00102. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	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.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000907176.1		c.325_336dupGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 15	ENSP00000577235.1

Frequencies

GnomAD3 genomes AF: 0.000923 AC: 139 AN: 150568 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000987

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00241

GnomAD2 exomes AF: 0.000898 AC: 168 AN: 187002 AF XY: 0.000793

Gnomad AFR exome AF: 0.000288

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000635

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00121 AC: 1725 AN: 1425978 Hom.: 3 Cov.: 111 AF XY: 0.00116 AC XY: 818 AN XY: 707124

African (AFR) AF: 0.000547 AC: 18 AN: 32884

American (AMR) AF: 0.00132 AC: 52 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 24980

East Asian (EAS) AF: 0.000442 AC: 17 AN: 38440

South Asian (SAS) AF: 0.000361 AC: 30 AN: 83114

European-Finnish (FIN) AF: 0.000285 AC: 14 AN: 49196

Middle Eastern (MID) AF: 0.00283 AC: 13 AN: 4600

European-Non Finnish (NFE) AF: 0.00138 AC: 1510 AN: 1094612

Other (OTH) AF: 0.00115 AC: 68 AN: 58888

GnomAD4 genome AF: 0.000923 AC: 139 AN: 150676 Hom.: 1 Cov.: 0 AF XY: 0.000884 AC XY: 65 AN XY: 73548

African (AFR) AF: 0.000755 AC: 31 AN: 41050

American (AMR) AF: 0.000986 AC: 15 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4918

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4768

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10444

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 83 AN: 67538

Other (OTH) AF: 0.00238 AC: 5 AN: 2098

Alfa AF: 0.00112 Hom.: 4554

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

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;