rs149961458

chr7-70118220-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015570.4(AUTS2):c.611A>G(p.Glu204Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,594,876 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.10

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014653385).
• BP6: Variant 7-70118220-A-G is Benign according to our data. Variant chr7-70118220-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 377186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-70118220-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00134 (202/150934) while in subpopulation NFE AF= 0.00267 (181/67724). AF 95% confidence interval is 0.00235. There are 2 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUTS2	NM_015570.4	c.611A>G	p.Glu204Gly	missense_variant	3/19	ENST00000342771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUTS2	ENST00000342771.10	c.611A>G	p.Glu204Gly	missense_variant	3/19	1	NM_015570.4	P4

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 202 AN: 150828 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.00160 AC: 360 AN: 224908 Hom.: 0 AF XY: 0.00156 AC XY: 191 AN XY: 122238

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000306

Gnomad FIN exome AF: 0.000530

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00237 AC: 3416 AN: 1443942 Hom.: 8 Cov.: 31 AF XY: 0.00231 AC XY: 1657 AN XY: 718466

Gnomad4 AFR exome AF: 0.000220

Gnomad4 AMR exome AF: 0.000525

Gnomad4 ASJ exome AF: 0.000157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000397

Gnomad4 FIN exome AF: 0.000790

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00134 AC: 202 AN: 150934 Hom.: 2 Cov.: 30 AF XY: 0.00122 AC XY: 90 AN XY: 73738

Gnomad4 AFR AF: 0.000292

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000425

Gnomad4 FIN AF: 0.000288

Gnomad4 NFE AF: 0.00267

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.00229 Hom.: 1

Bravo AF: 0.00131

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00171 AC: 208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AUTS2: BS1 -

Autism spectrum disorder due to AUTS2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

AUTS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D;T;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.69	T
Polyphen		0.93	.;P;P;.;.
Vest4		0.63, 0.56, 0.75
MVP		0.14
MPC		1.3
ClinPred		0.041	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.21

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: rs149961458; hg19: chr7-69583206;