rs143679158

Variant names:

• chr7-70764784-A-G
• rs143679158
• NM_015570.4:c.1247A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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:1 B:2
• Conservation: PhyloP100: 6.22
• Publications: 2 publications found

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]

AUTS2 Gene-Disease associations (from GenCC):

• autism spectrum disorder due to AUTS2 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 547994.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000112 (17/151266) while in subpopulation SAS AF = 0.000209 (1/4784). AF 95% confidence interval is 0.0000907. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015570.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	NM_015570.4	MANE Select	c.1247A>G	p.Gln416Arg	missense	Exon 8 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.1247A>G	p.Gln416Arg	missense	Exon 8 of 18	NP_001120703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.1247A>G	p.Gln416Arg	missense	Exon 8 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.1247A>G	p.Gln416Arg	missense	Exon 8 of 18	ENSP00000385263.2
	AUTS2	ENST00000644939.1		c.1244A>G	p.Gln415Arg	missense	Exon 8 of 19	ENSP00000496726.1

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

GnomAD2 exomes AF: 0.000130 AC: 20 AN: 153802 AF XY: 0.000135

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 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

African (AFR) AF: 0.00 AC: 0 AN: 17594

American (AMR) AF: 0.0000287 AC: 1 AN: 34870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20622

East Asian (EAS) AF: 0.00 AC: 0 AN: 32488

South Asian (SAS) AF: 0.000493 AC: 32 AN: 64852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48860

Middle Eastern (MID) AF: 0.000703 AC: 3 AN: 4270

European-Non Finnish (NFE) AF: 0.000182 AC: 74 AN: 407546

Other (OTH) AF: 0.000235 AC: 8 AN: 34006

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

African (AFR) AF: 0.0000730 AC: 3 AN: 41116

American (AMR) AF: 0.000132 AC: 2 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67810

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000241 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:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autism spectrum disorder due to AUTS2 deficiency Uncertain:1

Sep 08, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.030
Sift	Benign	0.79	T
Sift4G	Benign	0.52	T
Polyphen		0.95	P
Vest4		0.45
MVP		0.33
MPC		0.78
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.29
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs143679158; hg19: chr7-70229770;