7-70790590-GCCACCACCACCACCACCA-GCCACCACCACCA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. 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

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• 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 id is 1300716.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr7-70790590-GCCACCA-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.3395_3400delACCACC	p.His1132_His1133del	disruptive_inframe_deletion	Exon 19 of 19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.3395_3400delACCACC	p.His1132_His1133del	disruptive_inframe_deletion	Exon 19 of 19	1	NM_015570.4	ENSP00000344087.4

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

GnomAD3 exomes AF: 0.0000842 AC: 16 AN: 189948 Hom.: 0 AF XY: 0.000116 AC XY: 12 AN XY: 103280

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 SAS exome AF: 0.000277

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

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000934

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.000307

Gnomad4 FIN exome AF: 0.0000978

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.0000835

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

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AUTS2: BS2 -

Apr 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3395_3400del, results in the deletion of 2 amino acid(s) of the AUTS2 protein (p.His1132_His1133del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autism spectrum disorder due to AUTS2 deficiency Uncertain:1

Jan 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs538005366; hg19: chr7-70255576;