rs149961458

Variant names:

• chr7-70118220-A-G
• rs149961458
• NM_015570.4:c.611A>G

Variant summary

Our verdict is Benign. The variant received -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:10
• Conservation: PhyloP100: 6.10
• Publications: 4 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 -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 Benign/Likely_benign. ClinVar VariationId is 377186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 202 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	NM_015570.4	MANE Select	c.611A>G	p.Glu204Gly	missense	Exon 3 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.611A>G	p.Glu204Gly	missense	Exon 3 of 18	NP_001120703.1	Q8WXX7-2
	AUTS2	NM_001127232.3		c.611A>G	p.Glu204Gly	missense	Exon 3 of 5	NP_001120704.1	Q8WXX7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.611A>G	p.Glu204Gly	missense	Exon 3 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.611A>G	p.Glu204Gly	missense	Exon 3 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000403018.3	TSL:1	c.611A>G	p.Glu204Gly	missense	Exon 3 of 5	ENSP00000385572.2	Q8WXX7-3

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

GnomAD2 exomes AF: 0.00160 AC: 360 AN: 224908 AF XY: 0.00156

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 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

African (AFR) AF: 0.000220 AC: 7 AN: 31846

American (AMR) AF: 0.000525 AC: 21 AN: 40036

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 4 AN: 25402

East Asian (EAS) AF: 0.00 AC: 0 AN: 39234

South Asian (SAS) AF: 0.000397 AC: 33 AN: 83090

European-Finnish (FIN) AF: 0.000790 AC: 42 AN: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00290 AC: 3204 AN: 1106160

Other (OTH) AF: 0.00177 AC: 105 AN: 59476

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

African (AFR) AF: 0.000292 AC: 12 AN: 41112

American (AMR) AF: 0.000198 AC: 3 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000425 AC: 2 AN: 4702

European-Finnish (FIN) AF: 0.000288 AC: 3 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00267 AC: 181 AN: 67724

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.00231 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	1	Autism spectrum disorder due to AUTS2 deficiency (1)
-	-	1	AUTS2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		6.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.24	T
Polyphen		0.93	P
Vest4		0.63
MVP		0.14
MPC		1.3
ClinPred		0.041	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.21
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs149961458; hg19: chr7-69583206;