NM_015570.4:c.50G>A

Variant names:

• chr7-69599703-G-A
• rs1792261573
• NM_015570.4:c.50G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015570.4(AUTS2):​c.50G>A​(p.Arg17Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000171 in 1,172,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• 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), Orphanet, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39977247).

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.50G>A	p.Arg17Gln	missense	Exon 1 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.50G>A	p.Arg17Gln	missense	Exon 1 of 18	NP_001120703.1	Q8WXX7-2
	AUTS2	NM_001127232.3		c.50G>A	p.Arg17Gln	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.50G>A	p.Arg17Gln	missense	Exon 1 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.50G>A	p.Arg17Gln	missense	Exon 1 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000403018.3	TSL:1	c.50G>A	p.Arg17Gln	missense	Exon 1 of 5	ENSP00000385572.2	Q8WXX7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000171 AC: 2 AN: 1172992 Hom.: 0 Cov.: 32 AF XY: 0.00000353 AC XY: 2 AN XY: 567130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23486

American (AMR) AF: 0.00 AC: 0 AN: 9994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16018

East Asian (EAS) AF: 0.00 AC: 0 AN: 27222

South Asian (SAS) AF: 0.00 AC: 0 AN: 35980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3196

European-Non Finnish (NFE) AF: 0.00000205 AC: 2 AN: 973936

Other (OTH) AF: 0.00 AC: 0 AN: 47618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.24
MutPred		0.36		Gain of methylation at K13 (P = 0.1704)
MVP		0.61
MPC		2.3
ClinPred		0.91	D
GERP RS		3.7
PromoterAI		-0.023	Neutral
Varity_R		0.24
gMVP		0.22
Mutation Taster		=85/15	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: rs1792261573; hg19: chr7-69064689;