7-69599738-G-A

Variant names:

• chr7-69599738-G-A
• rs2129067357
• NM_015570.4:c.85G>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.85G>A​(p.Gly29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

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]

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=0.35946873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.85G>A	p.Gly29Arg	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.85G>A	p.Gly29Arg	missense_variant	Exon 1 of 19	1	NM_015570.4	ENSP00000344087.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1179470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 571278

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 23296

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 8922

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 15448

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 27160

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 38086

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 37058

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 978422

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 47824

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 29 of the AUTS2 protein (p.Gly29Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.32
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.26	.;N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	.;D;D;T
Sift4G	Benign	0.45	.;T;T;D
Polyphen		1.0	.;D;D;.
Vest4		0.20, 0.17, 0.19
MutPred		0.42		Gain of methylation at G29 (P = 0.0012);Gain of methylation at G29 (P = 0.0012);Gain of methylation at G29 (P = 0.0012);Gain of methylation at G29 (P = 0.0012);
MVP		0.14
MPC		3.1
ClinPred		0.74	D
GERP RS		3.7
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

Publications

LitVar

Other links and lift over

dbSNP: rs2129067357; hg19: chr7-69064724;