11-46397889-C-T

Variant names:

• chr11-46397889-C-T
• NM_001387011.1:c.3458G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001387011.1(AMBRA1):​c.3458G>A​(p.Arg1153Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMBRA1 NM_001387011.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBRA1	NM_001387011.1	c.3458G>A	p.Arg1153Lys	missense_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	c.3458G>A	p.Arg1153Lys	missense_variant	Exon 18 of 18		NM_001387011.1	ENSP00000508322.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3188G>A (p.R1063K) alteration is located in exon 19 (coding exon 18) of the AMBRA1 gene. This alteration results from a G to A substitution at nucleotide position 3188, causing the arginine (R) at amino acid position 1063 to be replaced by a lysine (K). 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	0.26
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T;.;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.2	.;.;.;M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N;N;N;N;D;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Benign	0.099	T;T;D;T;D;T
Polyphen		0.97	D;.;D;P;.;D
Vest4		0.59
MutPred		0.32		.;.;.;Gain of ubiquitination at R1153 (P = 0.0128);.;.;
MVP		0.81
MPC		1.4
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-46419439;