chr7-69599738-G-C

Variant names:

• chr7-69599738-G-C
• rs2129067357
• NM_015570.4:c.85G>C

Variant summary

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

The NM_015570.4(AUTS2):​c.85G>C​(p.Gly29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000848 in 1,179,470 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G29G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• 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=0.35273033).

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.85G>C	p.Gly29Arg	missense	Exon 1 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.85G>C	p.Gly29Arg	missense	Exon 1 of 18	NP_001120703.1	Q8WXX7-2
	AUTS2	NM_001127232.3		c.85G>C	p.Gly29Arg	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.85G>C	p.Gly29Arg	missense	Exon 1 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.85G>C	p.Gly29Arg	missense	Exon 1 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000403018.3	TSL:1	c.85G>C	p.Gly29Arg	missense	Exon 1 of 5	ENSP00000385572.2	Q8WXX7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.48e-7 AC: 1 AN: 1179470 Hom.: 0 Cov.: 32 AF XY: 0.00000175 AC XY: 1 AN XY: 571278

⚠️ 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: 23296

American (AMR) AF: 0.00 AC: 0 AN: 8922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15448

East Asian (EAS) AF: 0.00 AC: 0 AN: 27160

South Asian (SAS) AF: 0.0000263 AC: 1 AN: 38086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 978422

Other (OTH) AF: 0.00 AC: 0 AN: 47824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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	Benign	0.32
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.45	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.42		Gain of methylation at G29 (P = 0.0012)
MVP		0.13
MPC		3.1
ClinPred		0.76	D
GERP RS		3.7
PromoterAI		0.034	Neutral
Varity_R		0.35
gMVP		0.10
Mutation Taster		=86/14	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: rs2129067357; hg19: chr7-69064724;