7-69599655-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate 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. 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.
• PS1: Another start lost variant in NM_015570.4 (AUTS2) was described as [Pathogenic] in ClinVar as 1174542
• 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	UniProt
AUTS2	NM_015570.4	c.2T>C	p.Met1?	start_lost	1/19	ENST00000342771.10

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 315392 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 167682

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

LINK:

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

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

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;