chr7-69599721-A-G

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.

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.68A>G	p.Glu23Gly	missense	Exon 1 of 19	NP_056385.1
	AUTS2	NM_001127231.3		c.68A>G	p.Glu23Gly	missense	Exon 1 of 18	NP_001120703.1
	AUTS2	NM_001127232.3		c.68A>G	p.Glu23Gly	missense	Exon 1 of 5	NP_001120704.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.68A>G	p.Glu23Gly	missense	Exon 1 of 19	ENSP00000344087.4
	AUTS2	ENST00000406775.6	TSL:1	c.68A>G	p.Glu23Gly	missense	Exon 1 of 18	ENSP00000385263.2
	AUTS2	ENST00000403018.3	TSL:1	c.68A>G	p.Glu23Gly	missense	Exon 1 of 5	ENSP00000385572.2

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		0.39	B
Vest4		0.21
MutPred		0.28		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;