11-46408704-G-T

Variant names:

• chr11-46408704-G-T
• rs142506605
• NM_001387011.1:c.3212C>A

Variant summary

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

The NM_001387011.1(AMBRA1):​c.3212C>A​(p.Thr1071Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000726 in 1,376,996 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. T1071I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: AMBRA1 NM_001387011.1 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3212C>A	p.Thr1071Asn	missense splice_region	Exon 17 of 18	NP_001373940.1	Q9C0C7-1
	AMBRA1	NM_001267782.2		c.3221C>A	p.Thr1074Asn	missense splice_region	Exon 19 of 20	NP_001254711.1	Q9C0C7-5
	AMBRA1	NM_001367468.1		c.3212C>A	p.Thr1071Asn	missense splice_region	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.3212C>A	p.Thr1071Asn	missense splice_region	Exon 17 of 18	ENSP00000508322.1	Q9C0C7-1
	AMBRA1	ENST00000534300.5	TSL:1	c.3032C>A	p.Thr1011Asn	missense splice_region	Exon 16 of 17	ENSP00000431926.1	Q9C0C7-2
	AMBRA1	ENST00000314845.7	TSL:1	c.2942C>A	p.Thr981Asn	missense splice_region	Exon 18 of 19	ENSP00000318313.3	Q9C0C7-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1376996 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 677136

⚠️ 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: 30794

American (AMR) AF: 0.00 AC: 0 AN: 34198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21816

East Asian (EAS) AF: 0.00 AC: 0 AN: 37344

South Asian (SAS) AF: 0.00 AC: 0 AN: 75076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1065098

Other (OTH) AF: 0.00 AC: 0 AN: 56340

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		0.28	B
Vest4		0.53
MutPred		0.18		Loss of phosphorylation at T1071 (P = 0.0062)
MVP		0.45
MPC		0.85
ClinPred		0.83	D
GERP RS		4.4
Varity_R		0.16
gMVP		0.51
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142506605; hg19: chr11-46430254;