rs3735260

Variant names:

• chr7-69599651-A-G
• rs3735260
• NM_015570.4:c.-3A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_015570.4(AUTS2):c.-3A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0846 (AC=109,796) in the gnomAD database across 1,297,190 control chromosomes, including 5,804 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.258. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1768 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4036 hom.)
• Consequence: AUTS2 NM_015570.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04
• Publications: 8 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: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -16 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2577 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_015570.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	NM_015570.4	MANE Select	c.-3A>G		5_prime_UTR	Exon 1 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.-3A>G		5_prime_UTR	Exon 1 of 18	NP_001120703.1	Q8WXX7-2
	AUTS2	NM_001127232.3		c.-3A>G		5_prime_UTR	Exon 1 of 5	NP_001120704.1	Q8WXX7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.-3A>G		5_prime_UTR	Exon 1 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.-3A>G		5_prime_UTR	Exon 1 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000403018.3	TSL:1	c.-3A>G		5_prime_UTR	Exon 1 of 5	ENSP00000385572.2	Q8WXX7-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.126	19102	1760	151634	32
GnomAD2 exomes	0.0568	497		8750
GnomAD4 exome	0.0791	90660	4036	1145448	32
GnomAD4 genome	0.126	19136	1768	151742	32
TOPMed (Bravo)	0.134	35340	3378	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0939	16784	1016	178814
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.119	279	24	2342
ChinaMAP Phase 1	0.0917
Denmark Genome	0.0600	18		300
GenomeAsia100K	0.101	351		3476
Korea4K (4,157 Koreans)	0.0710	515		7210
Qatari Genome	0.182	32		176
ToMMo 61KJPN (+60KJPN MNV)	0.0507	5762	132	113658
Turkish Variome	0.0784	121	6	1544
UK10K	0.0726	549		7562
WBBC (Westlake BioBank for Chinese) pilot	0.0782	701	32	8960

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.146	9074	62044	0.152	13556	89076

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	16
BayesDel_noAF	Benign	-	-0.59
CADD	Benign	-	19
DANN	Benign	-	0.83
GPN-Star LLR	N/A	-	7.7
GPN-Star score	N/A	-	3.3
Mutation Taster	N/A	polymorphism (auto)	300/0
PhyloP100	Benign	-	1.0
PromoterAI	N/A	Neutral	0.043

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

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: rs3735260;

hg19: chr7-69064637;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar