rs1792262777

Variant names:

• chr7-69599721-A-G
• rs1792262777
• NM_015570.4:c.68A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_015570.4(AUTS2):​c.68A>G​(p.Glu23Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,173,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.231917).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000162 (19/1173400) while in subpopulation NFE AF = 0.0000195 (19/975010). AF 95% confidence interval is 0.0000125. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.68A>G	p.Glu23Gly	missense_variant	Exon 1 of 19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.68A>G	p.Glu23Gly	missense_variant	Exon 1 of 19	1	NM_015570.4	ENSP00000344087.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000162 AC: 19 AN: 1173400 Hom.: 0 Cov.: 32 AF XY: 0.0000106 AC XY: 6 AN XY: 567532

African (AFR) AF: 0.00 AC: 0 AN: 23304

American (AMR) AF: 0.00 AC: 0 AN: 9042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15504

East Asian (EAS) AF: 0.00 AC: 0 AN: 27126

South Asian (SAS) AF: 0.00 AC: 0 AN: 36218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3206

European-Non Finnish (NFE) AF: 0.0000195 AC: 19 AN: 975010

Other (OTH) AF: 0.00 AC: 0 AN: 47612

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 23 of the AUTS2 protein (p.Glu23Gly). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	.;.;T;.
Eigen	Benign	-0.037
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;L;L;L
PhyloP100		3.3
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.67	.;N;N;N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	.;D;D;T
Sift4G	Benign	0.15	.;T;T;D
Polyphen		0.39	.;B;B;.
Vest4		0.21, 0.21
MutPred		0.28		Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);
MVP		0.13
MPC		2.5
ClinPred		0.84	D
GERP RS		3.7
PromoterAI		0.080	Neutral
Varity_R		0.19
gMVP		0.13
Mutation Taster		=71/29	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: rs1792262777; hg19: chr7-69064707;