NM_001387011.1:c.3286G>A

Variant names:

• chr11-46408630-C-T
• rs746646452
• NM_001387011.1:c.3286G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001387011.1(AMBRA1):​c.3286G>A​(p.Ala1096Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,456,580 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: AMBRA1 NM_001387011.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01057747).
• BP6: Variant 11-46408630-C-T is Benign according to our data. Variant chr11-46408630-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2221144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 21 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.3286G>A	p.Ala1096Thr	missense	Exon 17 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3295G>A	p.Ala1099Thr	missense	Exon 19 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3286G>A	p.Ala1096Thr	missense	Exon 17 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.3286G>A	p.Ala1096Thr	missense	Exon 17 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3106G>A	p.Ala1036Thr	missense	Exon 16 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.3016G>A	p.Ala1006Thr	missense	Exon 18 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000484 AC: 12 AN: 248080 AF XY: 0.0000522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000611

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1456580 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 724428

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.0000226 AC: 1 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 85804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108756

Other (OTH) AF: 0.000200 AC: 12 AN: 60098

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000357 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.052
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.38
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.53	N
PhyloP100		1.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.098		Gain of glycosylation at A1096 (P = 0.0158)
MVP		0.11
MPC		0.50
ClinPred		0.045	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.46
Mutation Taster		=90/10	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: rs746646452; hg19: chr11-46430180;