7-69599654-A-T

Variant names:

• chr7-69599654-A-T
• NM_015570.4:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000406775.6(AUTS2):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 ENST00000406775.6 initiator_codon
• 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, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 93 codons. Genomic position: 69599930. Lost 0.075 part of the original CDS.
• PS1: Another start lost variant in ENST00000406775.6 (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 rank	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 19	1	NM_015570.4	ENSP00000344087.4

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

Submissions by phenotype

Autism spectrum disorder due to AUTS2 deficiency Pathogenic:1

Jul 08, 2020

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.026	.;.;T;.
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
PROVEAN	Benign	-0.33	.;N;N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;T
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;