7-70790653-G-T

Variant names:

• chr7-70790653-G-T
• rs150926322
• NM_015570.4:c.3437G>T

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.3437G>T​(p.Gly1146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,212 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G1146R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (108 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.26
• Publications: 5 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=0.004080683).
• BP6: Variant 7-70790653-G-T is Benign according to our data. Variant chr7-70790653-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376956.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 = 0.00884 (1345/152198) while in subpopulation NFE AF = 0.0137 (932/68002). AF 95% confidence interval is 0.013. There are 11 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1345 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.3437G>T	p.Gly1146Val	missense	Exon 19 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.3365G>T	p.Gly1122Val	missense	Exon 18 of 18	NP_001120703.1	Q8WXX7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.3437G>T	p.Gly1146Val	missense	Exon 19 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.3365G>T	p.Gly1122Val	missense	Exon 18 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000644939.1		c.3434G>T	p.Gly1145Val	missense	Exon 19 of 19	ENSP00000496726.1	A0A2R8Y8C6

Frequencies

GnomAD3 genomes AF: 0.00884 AC: 1345 AN: 152080 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00925 AC: 2262 AN: 244644 AF XY: 0.00924

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0110 AC: 16001 AN: 1461014 Hom.: 108 Cov.: 32 AF XY: 0.0109 AC XY: 7902 AN XY: 726830

African (AFR) AF: 0.00128 AC: 43 AN: 33474

American (AMR) AF: 0.00248 AC: 111 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 354 AN: 26086

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00518 AC: 447 AN: 86236

European-Finnish (FIN) AF: 0.0139 AC: 737 AN: 52926

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5768

European-Non Finnish (NFE) AF: 0.0123 AC: 13677 AN: 1111760

Other (OTH) AF: 0.00933 AC: 563 AN: 60368

GnomAD4 genome AF: 0.00884 AC: 1345 AN: 152198 Hom.: 11 Cov.: 32 AF XY: 0.00869 AC XY: 647 AN XY: 74412

African (AFR) AF: 0.00214 AC: 89 AN: 41548

American (AMR) AF: 0.00294 AC: 45 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4812

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0137 AC: 932 AN: 68002

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0119 Hom.: 32

Bravo AF: 0.00726

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.0103 AC: 1255

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.050
Sift	Benign	0.32	T
Sift4G	Benign	0.64	T
Polyphen		0.35	B
Vest4		0.19
MPC		0.54
ClinPred		0.0042	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150926322; hg19: chr7-70255639;