2-74529644-G-A

Position:

• chr2-74529644-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_181575.5(AUP1):​c.-15C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,554,500 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: AUP1 NM_181575.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.256

Genes affected

AUP1 (HGNC:891): (AUP1 lipid droplet regulating VLDL assembly factor) The protein encoded this gene is involved in several pathways including quality control of misfolded proteins in the endoplasmic reticulum and lipid droplet accumulation. Lipid droplets are organelles in the cytoplasm that store neutral lipids such as cholesterol esters and trigylycerides to prevent the overabundance of free cholesterol and fatty acids in cells, but also to act as storage for other metabolic processes, such as membrane biogenesis. Reduced expression of this gene results in reduced lipid droplet clustering, a function that is dependent on ubiquitination of the protein. This protein contains multiple domains including a hydrophobic N-terminal domain, an acetyltranferase domain, a ubiquitin-binding CUE domain, and a UBE2B2-binding domain (G2BR). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-74529644-G-A is Benign according to our data. Variant chr2-74529644-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 337119.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUP1	NM_181575.5	c.-15C>T		5_prime_UTR_variant	1/12	ENST00000377526.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUP1	ENST00000377526.4	c.-15C>T		5_prime_UTR_variant	1/12	1	NM_181575.5	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000463 AC: 71 AN: 153256 Hom.: 1 AF XY: 0.000504 AC XY: 42 AN XY: 83258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000315

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.000220 AC: 308 AN: 1402132 Hom.: 2 Cov.: 33 AF XY: 0.000238 AC XY: 165 AN XY: 692684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000407

Gnomad4 ASJ exome AF: 0.00619

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000221

Gnomad4 NFE exome AF: 0.0000904

Gnomad4 OTH exome AF: 0.000602

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74506

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000306

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease 13, autosomal dominant, susceptibility to Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs371791263; hg19: chr2-74756771;