7-70771588-C-G

Variant names:

• chr7-70771588-C-G
• rs199756061
• NM_015570.4:c.1774C>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.1774C>G​(p.Pro592Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,758 control chromosomes in the GnomAD database, including 46 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. P592S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00067 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.38
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0086167455).
• BP6: Variant 7-70771588-C-G is Benign according to our data. Variant chr7-70771588-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152332) while in subpopulation SAS AF = 0.0197 (95/4820). AF 95% confidence interval is 0.0165. There are 3 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 102 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.1774C>G	p.Pro592Ala	missense	Exon 11 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.1774C>G	p.Pro592Ala	missense	Exon 11 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.1774C>G	p.Pro592Ala	missense	Exon 11 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.1774C>G	p.Pro592Ala	missense	Exon 11 of 18	ENSP00000385263.2
	AUTS2	ENST00000644939.1		c.1771C>G	p.Pro591Ala	missense	Exon 11 of 19	ENSP00000496726.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00282 AC: 709 AN: 251434 AF XY: 0.00404

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00137 AC: 2003 AN: 1461426 Hom.: 43 Cov.: 30 AF XY: 0.00203 AC XY: 1477 AN XY: 727020

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0213 AC: 1839 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1111720

Other (OTH) AF: 0.00134 AC: 81 AN: 60364

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74470

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	AUTS2-related disorder (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.39
MPC		1.2
ClinPred		0.066	T
GERP RS		5.5
Varity_R		0.35
gMVP		0.72
Mutation Taster		=90/10	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: rs199756061; hg19: chr7-70236574; COSMIC: COSV61388163; COSMIC: COSV61388163;