dbSNP rs145428746: AMBRA1:p.Gly1135Val (chr11-46397943-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001387011.1(AMBRA1):c.3404G>T(p.Gly1135Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,586,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1135D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

AMBRA1
NM_001387011.1 missense, splice_region

Scores

Splicing: ADA: 0.9974

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBRA1	NM_001387011.1 link	c.3404G>T	p.Gly1135Val	missense_variant, splice_region_variant	Exon 18 of 18	ENST00000683756.1	NP_001373940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBRA1	ENST00000683756.1 link	c.3404G>T	p.Gly1135Val	missense_variant, splice_region_variant	Exon 18 of 18		NM_001387011.1	ENSP00000508322.1		Q9C0C7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000431

AC:

AN:

231784

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126444

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000933

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000349

AC:

AN:

1434684

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

.;T;.;T;T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

.;.;.;L;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

N;N;N;N;D;N

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Benign

0.062

T;T;T;T;D;T

Polyphen

0.99

D;.;P;P;.;D

Vest4

0.37

MutPred

0.30

.;.;.;Gain of sheet (P = 0.0061);.;.;

MVP

0.76

MPC

1.6

ClinPred

0.56

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over