rs1183739

Variant names:

• chr2-74529421-G-C
• rs1183739
• NM_181575.5:c.129C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181575.5(AUP1):​c.129C>G​(p.Leu43Leu) 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
• Publications: 15 publications found

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]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AUP1	NM_181575.5	c.129C>G	p.Leu43Leu	synonymous_variant	Exon 2 of 12	ENST00000377526.4	NP_853553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUP1	ENST00000377526.4	c.129C>G	p.Leu43Leu	synonymous_variant	Exon 2 of 12	1	NM_181575.5	ENSP00000366748.3

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

GnomAD2 exomes AF: 0.113 AC: 22950 AN: 202938 AF XY: 0.113

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 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

African (AFR) AF: 0.0218 AC: 722 AN: 33046

American (AMR) AF: 0.0531 AC: 2145 AN: 40366

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2826 AN: 25614

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38508

South Asian (SAS) AF: 0.0365 AC: 3045 AN: 83532

European-Finnish (FIN) AF: 0.250 AC: 12895 AN: 51548

Middle Eastern (MID) AF: 0.0891 AC: 511 AN: 5738

European-Non Finnish (NFE) AF: 0.163 AC: 178866 AN: 1098870

Other (OTH) AF: 0.127 AC: 7533 AN: 59406

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

African (AFR) AF: 0.0267 AC: 1112 AN: 41600

American (AMR) AF: 0.0651 AC: 997 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 381 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.0358 AC: 173 AN: 4832

European-Finnish (FIN) AF: 0.250 AC: 2651 AN: 10598

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10933 AN: 68016

Other (OTH) AF: 0.104 AC: 219 AN: 2114

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

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.051
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1183739; hg19: chr2-74756548; COSMIC: COSV51207655; COSMIC: COSV51207655;