11-46397730-G-C

Variant names:

• chr11-46397730-G-C
• rs1209472847
• NM_001387011.1:c.3617C>G

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.3617C>G​(p.Pro1206Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1206L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AMBRA1 NM_001387011.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• 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=0.20207262).

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.3617C>G	p.Pro1206Arg	missense	Exon 18 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3626C>G	p.Pro1209Arg	missense	Exon 20 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3617C>G	p.Pro1206Arg	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.3617C>G	p.Pro1206Arg	missense	Exon 18 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3437C>G	p.Pro1146Arg	missense	Exon 17 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.3347C>G	p.Pro1116Arg	missense	Exon 19 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460864 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.14	B
Vest4		0.12
MutPred		0.14		Loss of glycosylation at T1203 (P = 0.0483)
MVP		0.27
MPC		0.80
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.47
Mutation Taster		=61/39	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: rs1209472847; hg19: chr11-46419280;