14-53152762-TGCCGCC-TGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr14-53152762-T-TGCCGCCGCCGCCGCC
• rs55671452
• NM_001160148.2:c.336_337insGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS1

The NM_001160148.2(DDHD1):​c.336_337insGGCGGCGGCGGCGGC​(p.Gly112_Ser113insGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00025 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDHD1 NM_001160148.2 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.972

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001160148.2.
• BP6: Variant 14-53152762-T-TGCCGCCGCCGCCGCC is Benign according to our data. Variant chr14-53152762-T-TGCCGCCGCCGCCGCC is described in ClinVar as [Likely_benign]. Clinvar id is 464311.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000929 (140/150678) while in subpopulation AFR AF= 0.003 (123/41052). AF 95% confidence interval is 0.00257. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDHD1	NM_001160148.2	c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	ENST00000673822.2	NP_001153620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDHD1	ENST00000673822.2	c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13		NM_001160148.2	ENSP00000500986.2
DDHD1	ENST00000357758.3	c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 12	1		ENSP00000350401.3
DDHD1	ENST00000395606.5	c.336_337insGGCGGCGGCGGCGGC	p.Gly112_Ser113insGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 13	2		ENSP00000378970.1
DDHD1	ENST00000673930.1	c.-148_-147insGGCGGCGGCGGCGGC		upstream_gene_variant				ENSP00000501087.1

Frequencies

GnomAD3 genomes AF: 0.000930 AC: 140 AN: 150570 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000299 AC: 56 AN: 187002 Hom.: 0 AF XY: 0.000261 AC XY: 27 AN XY: 103428

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000193

Gnomad FIN exome AF: 0.000357

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.000417

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000255 AC: 363 AN: 1425976 Hom.: 1 Cov.: 111 AF XY: 0.000243 AC XY: 172 AN XY: 707122

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.000153

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.000144

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.000306

GnomAD4 genome AF: 0.000929 AC: 140 AN: 150678 Hom.: 0 Cov.: 0 AF XY: 0.000897 AC XY: 66 AN XY: 73548

Gnomad4 AFR AF: 0.00300

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.000629

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000477

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 28 Benign:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55671452; hg19: chr14-53619480;