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7-69599654-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_015570.4(AUTS2):c.1A>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AUTS2
NM_015570.4 start_lost

Scores

3
2
6

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.98
Variant links:
Genes affected
AUTS2 (HGNC:14262): (activator of transcription and developmental regulator AUTS2) This gene has been implicated in neurodevelopment and as a candidate gene for numerous neurological disorders, including autism spectrum disorders, intellectual disability, and developmental delay. Mutations in this gene have also been associated with non-neurological disorders, such as acute lymphoblastic leukemia, aging of the skin, early-onset androgenetic alopecia, and certain cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_015570.4 (AUTS2) was described as [Pathogenic] in ClinVar as 1033782
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-69599654-A-T is Pathogenic according to our data. Variant chr7-69599654-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1174542.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AUTS2NM_015570.4 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/19 ENST00000342771.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AUTS2ENST00000342771.10 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/191 NM_015570.4 P4Q8WXX7-1
AUTS2ENST00000406775.6 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/181 Q8WXX7-2
AUTS2ENST00000403018.3 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/51 Q8WXX7-3
AUTS2ENST00000644939.1 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/19 A1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autism spectrum disorder due to AUTS2 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Heidelberg UniversityJul 08, 2020The variant leads to a loss of the start codon (PVS1), it was not found in DNA extracted from the parents' blood samples (PS2), the variant is absent from controls (gnomAD; PM2); therefore we classified it as pathogenic according to ACMG criteria. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
Cadd
Benign
22
Dann
Benign
0.95
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.012
FATHMM_MKL
Benign
0.47
N
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D
Polyphen
0.021
.;B;B;.
Vest4
0.65, 0.70, 0.70
MutPred
0.77
Gain of catalytic residue at M1 (P = 0.0494);Gain of catalytic residue at M1 (P = 0.0494);Gain of catalytic residue at M1 (P = 0.0494);Gain of catalytic residue at M1 (P = 0.0494);
MVP
0.82
ClinPred
0.99
D
GERP RS
3.6
Varity_R
0.82
gMVP
0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-69064640; API