rs200189077

Variant names:

• chr7-69599664-C-T
• rs200189077
• NM_015570.4:c.11C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-69599664-C-T
• chr7-69599664-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015570.4(AUTS2):​c.11C>T​(p.Pro4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0046 in 1,304,368 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.82
• Publications: 4 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), Orphanet, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038175583).
• BP6: Variant 7-69599664-C-T is Benign according to our data. Variant chr7-69599664-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 975656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00289 (440/152146) while in subpopulation NFE AF = 0.00512 (348/67966). AF 95% confidence interval is 0.00468. There are 2 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 440 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	NM_015570.4	MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.11C>T	p.Pro4Leu	missense	Exon 1 of 18	NP_001120703.1	Q8WXX7-2
	AUTS2	NM_001127232.3		c.11C>T	p.Pro4Leu	missense	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.11C>T	p.Pro4Leu	missense	Exon 1 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.11C>T	p.Pro4Leu	missense	Exon 1 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000403018.3	TSL:1	c.11C>T	p.Pro4Leu	missense	Exon 1 of 5	ENSP00000385572.2	Q8WXX7-3

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00341 AC: 38 AN: 11154 AF XY: 0.00368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000211

Gnomad NFE exome AF: 0.00609

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.00483 AC: 5563 AN: 1152222 Hom.: 22 Cov.: 32 AF XY: 0.00471 AC XY: 2610 AN XY: 554422

African (AFR) AF: 0.000990 AC: 23 AN: 23236

American (AMR) AF: 0.00197 AC: 18 AN: 9142

Ashkenazi Jewish (ASJ) AF: 0.00533 AC: 82 AN: 15394

East Asian (EAS) AF: 0.00 AC: 0 AN: 27018

South Asian (SAS) AF: 0.000280 AC: 9 AN: 32142

European-Finnish (FIN) AF: 0.000544 AC: 18 AN: 33080

Middle Eastern (MID) AF: 0.000321 AC: 1 AN: 3112

European-Non Finnish (NFE) AF: 0.00546 AC: 5256 AN: 962466

Other (OTH) AF: 0.00335 AC: 156 AN: 46632

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152146 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74366

African (AFR) AF: 0.000842 AC: 35 AN: 41548

American (AMR) AF: 0.00124 AC: 19 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5106

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00512 AC: 348 AN: 67966

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00390 Hom.: 0

Bravo AF: 0.00296

ExAC AF: 0.000722 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	AUTS2-related disorder (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.47
MPC		2.6
ClinPred		0.067	T
GERP RS		3.6
PromoterAI		0.041	Neutral
Varity_R		0.25
gMVP		0.16
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200189077; hg19: chr7-69064650; COSMIC: COSV61410988; COSMIC: COSV61410988;