rs767529359

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_015570.4(AUTS2):​c.1295C>A​(p.Pro432His) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,346,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 22)
Exomes 𝑓: 0.00011 ( 4 hom. )

Consequence

AUTS2
NM_015570.4 missense

Scores

1
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 7.03
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 Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.085603684).
BP6
Variant 7-70764832-C-A is Benign according to our data. Variant chr7-70764832-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425414.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00036 (53/147226) while in subpopulation AMR AF= 0.00231 (34/14696). AF 95% confidence interval is 0.0017. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AUTS2NM_015570.4 linkc.1295C>A p.Pro432His missense_variant Exon 8 of 19 ENST00000342771.10 NP_056385.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AUTS2ENST00000342771.10 linkc.1295C>A p.Pro432His missense_variant Exon 8 of 19 1 NM_015570.4 ENSP00000344087.4 Q8WXX7-1

Frequencies

GnomAD3 genomes
AF:
0.000360
AC:
53
AN:
147226
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.000254
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00231
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000105
Gnomad OTH
AF:
0.00101
GnomAD3 exomes
AF:
0.000212
AC:
36
AN:
170110
Hom.:
0
AF XY:
0.000221
AC XY:
20
AN XY:
90474
show subpopulations
Gnomad AFR exome
AF:
0.000300
Gnomad AMR exome
AF:
0.000997
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.000211
GnomAD4 exome
AF:
0.000110
AC:
132
AN:
1199624
Hom.:
4
Cov.:
19
AF XY:
0.000101
AC XY:
61
AN XY:
601326
show subpopulations
Gnomad4 AFR exome
AF:
0.000249
Gnomad4 AMR exome
AF:
0.000707
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:
0.0000907
Gnomad4 OTH exome
AF:
0.000310
GnomAD4 genome
AF:
0.000360
AC:
53
AN:
147226
Hom.:
0
Cov.:
22
AF XY:
0.000433
AC XY:
31
AN XY:
71606
show subpopulations
Gnomad4 AFR
AF:
0.000254
Gnomad4 AMR
AF:
0.00231
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000105
Gnomad4 OTH
AF:
0.00101
Alfa
AF:
0.000121
Hom.:
0
ExAC
AF:
0.0000844
AC:
10

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 28, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2016- -
Autism spectrum disorder due to AUTS2 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
AUTS2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 15, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
.;.;T;.;.
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.086
T;T;T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Uncertain
2.2
.;M;M;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.6
.;D;D;.;.
REVEL
Uncertain
0.31
Sift
Uncertain
0.0010
.;D;D;.;.
Sift4G
Uncertain
0.0020
.;D;D;D;D
Polyphen
1.0
.;D;D;.;.
Vest4
0.80, 0.72
MVP
0.29
MPC
1.3
ClinPred
0.11
T
GERP RS
5.2
Varity_R
0.32
gMVP
0.46

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: rs767529359; hg19: chr7-70229818; COSMIC: COSV99048150; COSMIC: COSV99048150; API