NM_001160148.2:c.*134A>G

Variant names:

• chr14-53046634-T-C
• rs140975422
• NM_001160148.2:c.*134A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001160148.2(DDHD1):​c.*134A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 527,050 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: DDHD1 NM_001160148.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76
• Publications: 0 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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 28

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-53046634-T-C is Benign according to our data. Variant chr14-53046634-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1198656.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (718/152188) while in subpopulation AFR AF = 0.0165 (686/41528). AF 95% confidence interval is 0.0155. There are 8 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.*134A>G		3_prime_UTR	Exon 13 of 13	NP_001153620.1	Q8NEL9-1
	DDHD1	NM_001160147.2		c.*134A>G		3_prime_UTR	Exon 13 of 13	NP_001153619.1	Q8NEL9-4
	DDHD1	NM_030637.3		c.*134A>G		3_prime_UTR	Exon 12 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.*134A>G		3_prime_UTR	Exon 13 of 13	ENSP00000500986.2	Q8NEL9-1
	DDHD1	ENST00000357758.3	TSL:1	c.*134A>G		3_prime_UTR	Exon 12 of 12	ENSP00000350401.3	Q8NEL9-2
	DDHD1	ENST00000556027.5	TSL:1	n.3344A>G		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152070 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000429 AC: 161 AN: 374862 Hom.: 2 Cov.: 6 AF XY: 0.000324 AC XY: 62 AN XY: 191182

African (AFR) AF: 0.0150 AC: 133 AN: 8894

American (AMR) AF: 0.0000992 AC: 1 AN: 10080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10302

East Asian (EAS) AF: 0.00 AC: 0 AN: 24080

South Asian (SAS) AF: 0.0000898 AC: 1 AN: 11140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1652

European-Non Finnish (NFE) AF: 0.0000320 AC: 8 AN: 250358

Other (OTH) AF: 0.000883 AC: 18 AN: 20390

GnomAD4 genome AF: 0.00472 AC: 718 AN: 152188 Hom.: 8 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74412

African (AFR) AF: 0.0165 AC: 686 AN: 41528

American (AMR) AF: 0.00118 AC: 18 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00333 Hom.: 2

Bravo AF: 0.00511

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		1.8

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: rs140975422; hg19: chr14-53513352;