rs143679158

Positions:

• chr7-70764784-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015570.4(AUTS2):​c.1247A>G​(p.Gln416Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 816,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.22

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064305186).
• BP6: Variant 7-70764784-A-G is Benign according to our data. Variant chr7-70764784-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547994.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.1247A>G	p.Gln416Arg	missense_variant	8/19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.1247A>G	p.Gln416Arg	missense_variant	8/19	1	NM_015570.4	ENSP00000344087	P4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151148 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000130 AC: 20 AN: 153802 Hom.: 0 AF XY: 0.000135 AC XY: 11 AN XY: 81276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000177 AC: 118 AN: 665108 Hom.: 0 Cov.: 9 AF XY: 0.000210 AC XY: 74 AN XY: 352780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000493

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151266 Hom.: 0 Cov.: 30 AF XY: 0.0000541 AC XY: 4 AN XY: 73912

Gnomad4 AFR AF: 0.0000730

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000228 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000370 AC: 3

ExAC AF: 0.0000909 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 416 of the AUTS2 protein (p.Gln416Arg). This variant is present in population databases (rs143679158, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 547994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AUTS2 protein function with a negative predictive value of 80%. 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -

Autism spectrum disorder due to AUTS2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.019	.;.;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.79	.;N;N;.;.
REVEL	Benign	0.030
Sift	Benign	0.79	.;T;T;.;.
Sift4G	Benign	0.52	.;T;T;T;T
Polyphen		0.95	.;P;P;.;.
Vest4		0.45, 0.35
MVP		0.33
MPC		0.78
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143679158; hg19: chr7-70229770;