7-69599654-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_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 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98

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]

ACMG classification

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
AUTS2	NM_015570.4	c.1A>T	p.Met1?	start_lost	1/19	ENST00000342771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUTS2	ENST00000342771.10	c.1A>T	p.Met1?	start_lost	1/19	1	NM_015570.4	P4
AUTS2	ENST00000406775.6	c.1A>T	p.Met1?	start_lost	1/18	1
AUTS2	ENST00000403018.3	c.1A>T	p.Met1?	start_lost	1/5	1
AUTS2	ENST00000644939.1	c.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:

Submissions by phenotype

Autism spectrum disorder due to AUTS2 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Heidelberg University

Jul 08, 2020

The 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;