11-46397493-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001387011.1(AMBRA1):​c.3854G>C​(p.Arg1285Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,527,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AMBRA1 NM_001387011.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09756839).
• BS2: High AC in GnomAd4 at 5 AD gene.

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>C	p.Arg1285Thr	missense	Exon 18 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3863G>C	p.Arg1288Thr	missense	Exon 20 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3854G>C	p.Arg1285Thr	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>C	p.Arg1285Thr	missense	Exon 18 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3674G>C	p.Arg1225Thr	missense	Exon 17 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.3584G>C	p.Arg1195Thr	missense	Exon 19 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 32

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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000266 AC: 5 AN: 188286 AF XY: 0.0000404

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 160 AN: 1374950 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 82 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: 0.00 AC: 0 AN: 38802

South Asian (SAS) AF: 0.000166 AC: 12 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: 0.000136 AC: 145 AN: 1067634

Other (OTH) AF: 0.0000531 AC: 3 AN: 56524

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000420 AC: 5

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	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.48
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.085
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.40	T
Polyphen		0.0040	B
Vest4		0.12
MVP		0.36
MPC		0.82
ClinPred		0.091	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.35
Mutation Taster		=85/15	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;