chr2-74529421-G-C

Position:

• chr2-74529421-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181575.5(AUP1):​c.129C>G​(p.Leu43=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,588,962 control chromosomes in the GnomAD database, including 18,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1323 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17212 hom.)
• Consequence: AUP1 NM_181575.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0510

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-74529421-G-C is Benign according to our data. Variant chr2-74529421-G-C is described in ClinVar as [Benign]. Clinvar id is 337116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.051 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUP1	NM_181575.5	c.129C>G	p.Leu43=	synonymous_variant	2/12	ENST00000377526.4	NP_853553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AUP1	ENST00000377526.4	c.129C>G	p.Leu43=	synonymous_variant	2/12	1	NM_181575.5	ENSP00000366748	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16561 AN: 152216 Hom.: 1324 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.113 AC: 22950 AN: 202938 Hom.: 1831 AF XY: 0.113 AC XY: 12403 AN XY: 110194

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.000204

Gnomad SAS exome AF: 0.0351

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.145 AC: 208548 AN: 1436628 Hom.: 17212 Cov.: 35 AF XY: 0.142 AC XY: 101399 AN XY: 712454

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.0531

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.000130

Gnomad4 SAS exome AF: 0.0365

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.109 AC: 16552 AN: 152334 Hom.: 1323 Cov.: 33 AF XY: 0.109 AC XY: 8125 AN XY: 74486

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.0651

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.104

Alfa AF: 0.142 Hom.: 578

Bravo AF: 0.0913

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.6
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1183739; hg19: chr2-74756548; COSMIC: COSV51207655; COSMIC: COSV51207655;