chr7-70790590-G-GCCACCACCA

Variant names:

• chr7-70790590-G-GCCACCACCA
• rs538005366
• NM_015570.4:c.3392_3400dupACCACCACC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_015570.4(AUTS2):​c.3392_3400dupACCACCACC​(p.His1131_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 0.000035 in 1,600,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: AUTS2 NM_015570.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015570.4
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000856 (13/151886) while in subpopulation EAS AF = 0.000786 (4/5090). AF 95% confidence interval is 0.000268. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 13 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.3392_3400dupACCACCACC	p.His1131_His1133dup	disruptive_inframe_insertion	Exon 19 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.3320_3328dupACCACCACC	p.His1107_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.3392_3400dupACCACCACC	p.His1131_His1133dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.3320_3328dupACCACCACC	p.His1107_His1109dup	disruptive_inframe_insertion	Exon 18 of 18	ENSP00000385263.2
	AUTS2	ENST00000644939.1		c.3389_3397dupACCACCACC	p.His1130_His1132dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000496726.1

Frequencies

GnomAD3 genomes AF: 0.0000857 AC: 13 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000784

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000297 AC: 43 AN: 1448952 Hom.: 0 Cov.: 32 AF XY: 0.0000264 AC XY: 19 AN XY: 719806

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000602 AC: 2 AN: 33204

American (AMR) AF: 0.00 AC: 0 AN: 42814

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

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38740

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51154

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

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1106936

Other (OTH) AF: 0.0000668 AC: 4 AN: 59892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000444089), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151886 Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6 AN XY: 74206

African (AFR) AF: 0.0000723 AC: 3 AN: 41476

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

East Asian (EAS) AF: 0.000786 AC: 4 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000734 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (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: COSV100719738; COSMIC: COSV100719738;