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: 10 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

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		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	Prot: NP_056385.1 UniProt:
	AUTS2 NM_001127231.3		c.-3A>G	5_prime_UTR	Exon 1 of 18	Prot: NP_001120703.1 UniProt:
	AUTS2 NM_001127232.3		c.-3A>G	5_prime_UTR	Exon 1 of 5	Prot: NP_001120704.1 UniProt:

AUTS2 NM_015570.4

MANE Select

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 19

5_prime_UTR

Prot: NP_056385.1UniProt: Q8WXX7-1

AUTS2 NM_001127231.3

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 18

5_prime_UTR

Prot: NP_001120703.1UniProt: Q8WXX7-2

AUTS2 NM_001127232.3

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 5

5_prime_UTR

Prot: NP_001120704.1UniProt: Q8WXX7-3

Ensembl Transcripts

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

AUTS2 ENST00000342771.10

TSL:1MANE Select

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 19

5_prime_UTR

Prot: ENSP00000344087.4UniProt: Q8WXX7-1

AUTS2 ENST00000406775.6

TSL:1

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 18

5_prime_UTR

Prot: ENSP00000385263.2UniProt: Q8WXX7-2

AUTS2 ENST00000403018.3

TSL:1

HGVSc / HGVSpc.-3A>G

Exon rankExon 1 of 5

5_prime_UTR

Prot: ENSP00000385572.2UniProt: 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	AF: 0.126	AC:19102	Hom:1760	AN:151634	Cov:32
GnomAD2 exomes	AF: 0.0568	AC:497	Hom:	AN:8750	Cov:
GnomAD4 exome	AF: 0.0791	AC:90660	Hom:4036	AN:1145448	Cov:32
GnomAD4 genome	AF: 0.126	AC:19136	Hom:1768	AN:151742	Cov:32
TOPMed (Bravo)	AF: 0.134	AC:35340	Hom:3378	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0939	AC:16784	Hom:1016	AN:178814	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.119	AC:279	Hom:24	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0917	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0600	AC:18	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.101	AC:351	Hom:	AN:3476	Cov:
Korea4K (4,157 Koreans)	AF: 0.0710	AC:515	Hom:	AN:7210	Cov:
Qatari Genome	AF: 0.182	AC:32	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0507	AC:5762	Hom:132	AN:113658	Cov:
Turkish Variome	AF: 0.0784	AC:121	Hom:6	AN:1544	Cov:
UK10K	AF: 0.0726	AC:549	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0782	AC:701	Hom:32	AN:8960	Cov:

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 pred.	Score	Prediction
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	300/0	polymorphism (auto)
PhyloP100	Benign	1.0
PromoterAI	N/A	0.043	Neutral

Showing 9 of 9 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3735260;

hg19: chr7-69064637;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar