7-69599717-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_015570.4(AUTS2):​c.64C>T​(p.Arg22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,173,092 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: 0.000011 ( 0 hom. )

Consequence

AUTS2
NM_015570.4 missense

Scores

5
4
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.82
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.39417452).
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AUTS2NM_015570.4 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 19 ENST00000342771.10 NP_056385.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AUTS2ENST00000342771.10 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 19 1 NM_015570.4 ENSP00000344087.4 Q8WXX7-1
AUTS2ENST00000406775.6 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 18 1 ENSP00000385263.2 Q8WXX7-2
AUTS2ENST00000403018.3 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 5 1 ENSP00000385572.2 Q8WXX7-3
AUTS2ENST00000644939.1 linkc.64C>T p.Arg22Trp missense_variant Exon 1 of 19 ENSP00000496726.1 A0A2R8Y8C6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000111
AC:
13
AN:
1173092
Hom.:
0
Cov.:
32
AF XY:
0.00000881
AC XY:
5
AN XY:
567314
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000123
Gnomad4 OTH exome
AF:
0.0000210
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 18, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the AUTS2 protein (p.Arg22Trp). 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. ClinVar contains an entry for this variant (Variation ID: 1205753). 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 20, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Benign
-0.37
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;.;T;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Benign
0.33
N
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Benign
0.39
T;T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.1
.;L;L;L
PrimateAI
Pathogenic
0.98
D
PROVEAN
Benign
-1.6
.;N;N;D
REVEL
Benign
0.14
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Pathogenic
0.0010
.;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.28, 0.28, 0.47
MutPred
0.29
Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);
MVP
0.29
MPC
2.6
ClinPred
0.96
D
GERP RS
3.7
Varity_R
0.19
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1263138285; hg19: chr7-69064703; API