Genetic Variant NM_001387011.1:c.3212C>T (chr11-46408704-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001387011.1(AMBRA1):c.3212C>T(p.Thr1071Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000955 in 1,529,368 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

AMBRA1
NM_001387011.1 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

Publications

0 publications found

Variant links:

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]

AMBRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021608382).

BS2

High AC in GnomAd4 at 78 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMBRA1	NM_001387011.1	MANE Select	c.3212C>T	p.Thr1071Ile	missense splice_region	Exon 17 of 18	NP_001373940.1	Q9C0C7-1
AMBRA1	NM_001267782.2		c.3221C>T	p.Thr1074Ile	missense splice_region	Exon 19 of 20	NP_001254711.1	Q9C0C7-5
AMBRA1	NM_001367468.1		c.3212C>T	p.Thr1071Ile	missense splice_region	Exon 17 of 18	NP_001354397.1	Q9C0C7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMBRA1	ENST00000683756.1	MANE Select	c.3212C>T	p.Thr1071Ile	missense splice_region	Exon 17 of 18	ENSP00000508322.1	Q9C0C7-1
AMBRA1	ENST00000534300.5	TSL:1	c.3032C>T	p.Thr1011Ile	missense splice_region	Exon 16 of 17	ENSP00000431926.1	Q9C0C7-2
AMBRA1	ENST00000314845.7	TSL:1	c.2942C>T	p.Thr981Ile	missense splice_region	Exon 18 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000152

AC:

AN:

197504

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.0000402

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000494

AC:

AN:

1376996

Hom.:

Cov.:

AF XY:

0.0000266

AC XY:

AN XY:

677136

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

30794

American (AMR)

AF:

0.0000292

AC:

AN:

34198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21816

East Asian (EAS)

AF:

0.00

AC:

AN:

37344

South Asian (SAS)

AF:

0.00

AC:

AN:

75076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5372

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065098

Other (OTH)

AF:

0.0000887

AC:

AN:

56340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000512

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00704

Hom.:

730

Bravo

AF:

0.000476

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.044

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.8

PhyloP100

6.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

0.57

Vest4

0.62

MVP

0.35

MPC

1.1

ClinPred

0.10

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.56

Mutation Taster

=64/36

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over