dbSNP rs1183739: AUP1:p.Leu43Leu (chr2-74529421-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0510

Publications

15 publications found

Variant links:

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]

AUP1 links:

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, Labcorp Genetics (formerly Invitae), ClinGen

HTRA2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_181575.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181575.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AUP1	NM_181575.5	MANE Select	c.129C>G	p.Leu43Leu	synonymous	Exon 2 of 12	NP_853553.1	Q9Y679-2
HTRA2	NM_001321727.1		c.-586G>C		5_prime_UTR	Exon 1 of 7	NP_001308656.1	O43464-3
HTRA2	NM_001321728.1		c.-586G>C		5_prime_UTR	Exon 1 of 7	NP_001308657.1	A0A8Q3SIX7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AUP1	ENST00000377526.4	TSL:1 MANE Select	c.129C>G	p.Leu43Leu	synonymous	Exon 2 of 12	ENSP00000366748.3	Q9Y679-2
AUP1	ENST00000425118.5	TSL:1	n.129C>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000403430.1	Q9Y679-3
AUP1	ENST00000463900.5	TSL:1	n.197C>G		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16561

AN:

152216

Hom.:

1324

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.142

AC XY:

101399

AN XY:

712454

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

12411

24823

37234

49646

62057

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6176

12352

18528

24704

30880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.109

AC:

16552

AN:

152334

Hom.:

1323

Cov.:

AF XY:

0.109

AC XY:

8125

AN XY:

74486

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10933

AN:

68016

Other (OTH)

AF:

0.104

AC:

219

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

742

1484

2226

2968

3710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.142

Hom.:

578

Bravo

AF:

0.0913

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Parkinson disease 13, autosomal dominant, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.6

(source)

DANN

Benign

0.92

PhyloP100

-0.051

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=298/2

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over