7-69599655-T-C

Position:

• chr7-69599655-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015570.4(AUTS2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AUTS2 NM_015570.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.25

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-69599655-T-C is Pathogenic according to our data. Variant chr7-69599655-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1033782.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.2T>C	p.Met1?	start_lost	1/19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.2T>C	p.Met1?	start_lost	1/19	1	NM_015570.4	ENSP00000344087	P4
AUTS2	ENST00000406775.6	c.2T>C	p.Met1?	start_lost	1/18	1		ENSP00000385263
AUTS2	ENST00000403018.3	c.2T>C	p.Met1?	start_lost	1/5	1		ENSP00000385572
AUTS2	ENST00000644939.1	c.2T>C	p.Met1?	start_lost	1/19			ENSP00000496726	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1148492 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 552394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 23, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Defects in AUTS2 are the cause of Mental retardation, autosomal dominant 26 (MRD26) [MIM:615834], an autosomal dominant disorder characterized by intellectual disability, autism, developmental delay, short stature, microcephaly, cerebral palsy, kyphosis, and facial dysmorphisms [PMID 23332918] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.034	.;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.44	.;N;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.0030	.;B;B;.
Vest4		0.72, 0.70, 0.72
MutPred		0.77		Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);
MVP		0.52
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.80
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs1792258600; hg19: chr7-69064641;