Variant 11-46397730-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001387011.1(AMBRA1):c.3617C>T(p.Pro1206Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AMBRA1
NM_001387011.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.58

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17888784).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMBRA1	NM_001387011.1 linkuse as main transcript	c.3617C>T	p.Pro1206Leu	missense_variant	18/18	ENST00000683756.1	NP_001373940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMBRA1	ENST00000683756.1 linkuse as main transcript	c.3617C>T	p.Pro1206Leu	missense_variant	18/18		NM_001387011.1	ENSP00000508322	A1	Q9C0C7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249736

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460864

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.3347C>T (p.P1116L) alteration is located in exon 19 (coding exon 18) of the AMBRA1 gene. This alteration results from a C to T substitution at nucleotide position 3347, causing the proline (P) at amino acid position 1116 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

.;T;.;T;T;.

Eigen

Benign

0.026

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.4

.;.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

0.0030

B;.;B;B;.;B

Vest4

0.13

MutPred

0.068

.;.;.;Loss of glycosylation at P1206 (P = 0.0596);.;.;

MVP

0.24

MPC

0.56

ClinPred

0.79

GERP RS

5.2

Varity_R

0.31

gMVP

0.40

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over