Genetic Variant AMBRA1:p.Val1059Ile (chr11-46410310-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001387011.1(AMBRA1):c.3175G>A(p.Val1059Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

AMBRA1
NM_001387011.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Publications

0 publications found

Variant links:

Genes affected

AMBRA1 (HGNC:25990): (autophagy and beclin 1 regulator 1) Enables GTPase binding activity and ubiquitin protein ligase binding activity. Involved in macroautophagy; positive regulation of phosphatidylinositol 3-kinase activity; and response to mitochondrial depolarisation. Located in cytosol. Colocalizes with mitochondrion. Biomarker of multiple system atrophy. [provided by Alliance of Genome Resources, Apr 2022]

AMBRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10133442).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387011.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMBRA1	NM_001387011.1	MANE Select	c.3175G>A	p.Val1059Ile	missense	Exon 16 of 18	NP_001373940.1	Q9C0C7-1
AMBRA1	NM_001267782.2		c.3184G>A	p.Val1062Ile	missense	Exon 18 of 20	NP_001254711.1	Q9C0C7-5
AMBRA1	NM_001367468.1		c.3175G>A	p.Val1059Ile	missense	Exon 16 of 18	NP_001354397.1	Q9C0C7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMBRA1	ENST00000683756.1	MANE Select	c.3175G>A	p.Val1059Ile	missense	Exon 16 of 18	ENSP00000508322.1	Q9C0C7-1
AMBRA1	ENST00000534300.5	TSL:1	c.2995G>A	p.Val999Ile	missense	Exon 15 of 17	ENSP00000431926.1	Q9C0C7-2
AMBRA1	ENST00000314845.7	TSL:1	c.2905G>A	p.Val969Ile	missense	Exon 17 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251156

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0084

Eigen

Benign

-0.10

Eigen_PC

Benign

0.095

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.048

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.41

PhyloP100

2.9

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.28

REVEL

Benign

0.072

Sift

Benign

0.14

Sift4G

Benign

0.52

Polyphen

0.19

Vest4

0.26

MutPred

0.22

Gain of sheet (P = 0.0827)

MVP

0.38

MPC

0.46

ClinPred

0.23

GERP RS

4.9

Varity_R

0.088

gMVP

0.21

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over