7-70790590-GCCACCACCACCACCACCA-GCCACCACCACCACCACCACCACCA

Variant names:

• chr7-70790590-G-GCCACCA
• rs538005366
• NM_015570.4:c.3395_3400dupACCACC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_015570.4(AUTS2):​c.3395_3400dupACCACC​(p.His1132_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 0.00516 in 1,600,798 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (160 hom.)
• Consequence: AUTS2 NM_015570.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015570.4
• BP6: Variant 7-70790590-G-GCCACCA is Benign according to our data. Variant chr7-70790590-G-GCCACCA is described in ClinVar as Benign. ClinVar VariationId is 445607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

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.3395_3400dupACCACC	p.His1132_His1133dup	disruptive_inframe_insertion	Exon 19 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.3323_3328dupACCACC	p.His1108_His1109dup	disruptive_inframe_insertion	Exon 18 of 18	NP_001120703.1	Q8WXX7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.3395_3400dupACCACC	p.His1132_His1133dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.3323_3328dupACCACC	p.His1108_His1109dup	disruptive_inframe_insertion	Exon 18 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000644939.1		c.3392_3397dupACCACC	p.His1131_His1132dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000496726.1	A0A2R8Y8C6

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 800 AN: 151768 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0725

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.0102 AC: 1936 AN: 189948 AF XY: 0.0109

Gnomad AFR exome AF: 0.000975

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.0650

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00905

GnomAD4 exome AF: 0.00515 AC: 7462 AN: 1448916 Hom.: 160 Cov.: 32 AF XY: 0.00584 AC XY: 4207 AN XY: 719792

African (AFR) AF: 0.00111 AC: 37 AN: 33202

American (AMR) AF: 0.00196 AC: 84 AN: 42812

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

East Asian (EAS) AF: 0.0677 AC: 2621 AN: 38730

South Asian (SAS) AF: 0.0308 AC: 2608 AN: 84600

European-Finnish (FIN) AF: 0.00143 AC: 73 AN: 51152

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5748

European-Non Finnish (NFE) AF: 0.00134 AC: 1482 AN: 1106932

Other (OTH) AF: 0.00900 AC: 539 AN: 59892

GnomAD4 genome AF: 0.00527 AC: 800 AN: 151882 Hom.: 27 Cov.: 32 AF XY: 0.00592 AC XY: 439 AN XY: 74204

African (AFR) AF: 0.00193 AC: 80 AN: 41476

American (AMR) AF: 0.00177 AC: 27 AN: 15278

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

East Asian (EAS) AF: 0.0725 AC: 369 AN: 5088

South Asian (SAS) AF: 0.0399 AC: 190 AN: 4760

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 67914

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00110 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	AUTS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs538005366;

hg19: chr7-70255576;

COSMIC: COSV61420305;

COSMIC: COSV61420305;