chr11-46397889-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBRA1	NM_001387011.1	MANE Select	c.3458G>A	p.Arg1153Lys	missense	Exon 18 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3467G>A	p.Arg1156Lys	missense	Exon 20 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3458G>A	p.Arg1153Lys	missense	Exon 18 of 18	NP_001354397.1	Q9C0C7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBRA1	ENST00000683756.1	MANE Select	c.3458G>A	p.Arg1153Lys	missense	Exon 18 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3278G>A	p.Arg1093Lys	missense	Exon 17 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.3188G>A	p.Arg1063Lys	missense	Exon 19 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.099	T
Polyphen		0.97	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
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

hg19: chr11-46419439;