7-69599654-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS1_Moderate

The NM_015570.4(AUTS2):c.1A>G(p.Met1?) variant causes a start lost change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: Uncertain significance criteria provided, single submitter U: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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUTS2	NM_015570.4	c.1A>G	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>G	p.Met1?	start_lost	1/19	1	NM_015570.4	P4
AUTS2	ENST00000406775.6	c.1A>G	p.Met1?	start_lost	1/18	1
AUTS2	ENST00000403018.3	c.1A>G	p.Met1?	start_lost	1/5	1
AUTS2	ENST00000644939.1	c.1A>G	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: 314536 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 167088

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the AUTS2 mRNA. The next in-frame methionine is located at codon 93. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

D

BayesDel_noAF

Uncertain

0.070

Cadd

Benign

22

Dann

Uncertain

0.98

Eigen

Benign

-0.081

Eigen_PC

Benign

0.0074

FATHMM_MKL

Benign

0.58

D

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.96

D

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-1.1

T

MutationTaster

Benign

1.0

D;D;D

Polyphen

0.048

.;B;B;.

Vest4

0.70, 0.71, 0.74

MutPred

0.76

Loss of glycosylation at T5 (P = 0.2517);Loss of glycosylation at T5 (P = 0.2517);Loss of glycosylation at T5 (P = 0.2517);Loss of glycosylation at T5 (P = 0.2517);

MVP

0.81

ClinPred

0.99

D

GERP RS

3.6

Varity_R

0.81

gMVP

0.16

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;