7-70790590-GCCACCACCACCACCACCA-GCCACCACCACCA

Variant names:

• chr7-70790590-GCCACCA-G
• rs538005366
• NM_015570.4:c.3395_3400delACCACC

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.3395_3400delACCACC​(p.His1132_His1133del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000637 in 1,600,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: AUTS2 NM_015570.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.22
• 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-GCCACCA-G is Benign according to our data. Variant chr7-70790590-GCCACCA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1300716.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000988 (15/151772) while in subpopulation SAS AF = 0.000419 (2/4768). AF 95% confidence interval is 0.0000738. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 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.3395_3400delACCACC	p.His1132_His1133del	disruptive_inframe_deletion	Exon 19 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.3323_3328delACCACC	p.His1108_His1109del	disruptive_inframe_deletion	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.3395_3400delACCACC	p.His1132_His1133del	disruptive_inframe_deletion	Exon 19 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.3323_3328delACCACC	p.His1108_His1109del	disruptive_inframe_deletion	Exon 18 of 18	ENSP00000385263.2
	AUTS2	ENST00000644939.1		c.3392_3397delACCACC	p.His1131_His1132del	disruptive_inframe_deletion	Exon 19 of 19	ENSP00000496726.1

Frequencies

GnomAD3 genomes AF: 0.0000988 AC: 15 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000842 AC: 16 AN: 189948 AF XY: 0.000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000142

Gnomad FIN exome AF: 0.0000651

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000600 AC: 87 AN: 1448934 Hom.: 0 AF XY: 0.0000653 AC XY: 47 AN XY: 719796

African (AFR) AF: 0.0000301 AC: 1 AN: 33204

American (AMR) AF: 0.0000934 AC: 4 AN: 42814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38740

South Asian (SAS) AF: 0.000307 AC: 26 AN: 84616

European-Finnish (FIN) AF: 0.0000978 AC: 5 AN: 51144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1106928

Other (OTH) AF: 0.0000835 AC: 5 AN: 59892

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151772 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74082

African (AFR) AF: 0.0000967 AC: 4 AN: 41354

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4768

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Autism spectrum disorder due to AUTS2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2
Mutation Taster		=99/101	disease causing

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: COSV105907759; COSMIC: COSV105907759;