7-70790590-GCCACCACCACCACCACCA-GCCACCACCACCACCACCACCA

Variant names:

• chr7-70790590-G-GCCA
• rs538005366
• NM_015570.4:c.3398_3400dupACC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_015570.4(AUTS2):​c.3398_3400dupACC​(p.His1133dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00816 in 1,600,800 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (72 hom.)
• Consequence: AUTS2 NM_015570.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.930
• Publications: 6 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015570.4
• BP6: Variant 7-70790590-G-GCCA is Benign according to our data. Variant chr7-70790590-G-GCCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374065.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00624 (947/151882) while in subpopulation SAS AF = 0.0265 (126/4762). AF 95% confidence interval is 0.0227. There are 3 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 947 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.3398_3400dupACC	p.His1133dup	disruptive_inframe_insertion	Exon 19 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.3326_3328dupACC	p.His1109dup	disruptive_inframe_insertion	Exon 18 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.3398_3400dupACC	p.His1133dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.3326_3328dupACC	p.His1109dup	disruptive_inframe_insertion	Exon 18 of 18	ENSP00000385263.2
	AUTS2	ENST00000644939.1		c.3395_3397dupACC	p.His1132dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000496726.1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 947 AN: 151768 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000980

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00720

GnomAD2 exomes AF: 0.00898 AC: 1706 AN: 189948 AF XY: 0.0105

Gnomad AFR exome AF: 0.00230

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00858

Gnomad EAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00836 AC: 12111 AN: 1448918 Hom.: 72 Cov.: 32 AF XY: 0.00899 AC XY: 6471 AN XY: 719784

African (AFR) AF: 0.00244 AC: 81 AN: 33204

American (AMR) AF: 0.00577 AC: 247 AN: 42812

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 193 AN: 25848

East Asian (EAS) AF: 0.00137 AC: 53 AN: 38734

South Asian (SAS) AF: 0.0259 AC: 2187 AN: 84600

European-Finnish (FIN) AF: 0.00215 AC: 110 AN: 51154

Middle Eastern (MID) AF: 0.0268 AC: 154 AN: 5748

European-Non Finnish (NFE) AF: 0.00772 AC: 8540 AN: 1106930

Other (OTH) AF: 0.00912 AC: 546 AN: 59888

GnomAD4 genome AF: 0.00624 AC: 947 AN: 151882 Hom.: 3 Cov.: 32 AF XY: 0.00619 AC XY: 459 AN XY: 74206

African (AFR) AF: 0.00251 AC: 104 AN: 41474

American (AMR) AF: 0.00727 AC: 111 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.000982 AC: 5 AN: 5090

South Asian (SAS) AF: 0.0265 AC: 126 AN: 4762

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00785 AC: 533 AN: 67914

Other (OTH) AF: 0.00760 AC: 16 AN: 2104

Alfa AF: 0.00378 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autism spectrum disorder due to AUTS2 deficiency (1)
-	1	-	Autism;C0557874:Global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.93
Mutation Taster		=82/18	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs538005366; hg19: chr7-70255576; COSMIC: COSV61389707; COSMIC: COSV61389707;