11-46397493-C-A

Variant names:

• chr11-46397493-C-A
• rs143178975
• NM_001387011.1:c.3854G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387011.1(AMBRA1):​c.3854G>T​(p.Arg1285Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,374,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R1285T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: AMBRA1 NM_001387011.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19326624).

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.3854G>T	p.Arg1285Met	missense	Exon 18 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3863G>T	p.Arg1288Met	missense	Exon 20 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3854G>T	p.Arg1285Met	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.3854G>T	p.Arg1285Met	missense	Exon 18 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3674G>T	p.Arg1225Met	missense	Exon 17 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.3584G>T	p.Arg1195Met	missense	Exon 19 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1374950 Hom.: 0 Cov.: 31 AF XY: 0.00000297 AC XY: 2 AN XY: 673550

African (AFR) AF: 0.00 AC: 0 AN: 30854

American (AMR) AF: 0.00 AC: 0 AN: 32812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20430

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38802

South Asian (SAS) AF: 0.00 AC: 0 AN: 72410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067634

Other (OTH) AF: 0.00 AC: 0 AN: 56524

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.48
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.14	T
Polyphen		0.060	B
Vest4		0.33
MutPred		0.21		Loss of methylation at R1285 (P = 0.0238)
MVP		0.40
MPC		0.99
ClinPred		0.58	D
GERP RS		3.9
Varity_R		0.12
gMVP		0.42
Mutation Taster		=89/11	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

dbSNP: rs143178975; hg19: chr11-46419043;