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GeneBe

7-69599664-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015570.4(AUTS2):c.11C>T(p.Pro4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0046 in 1,304,368 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0048 ( 22 hom. )

Consequence

AUTS2
NM_015570.4 missense

Scores

1
4
7

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.82
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0038175583).
BP6
Variant 7-69599664-C-T is Benign according to our data. Variant chr7-69599664-C-T is described in ClinVar as [Benign]. Clinvar id is 975656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-69599664-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00289 (440/152146) while in subpopulation NFE AF= 0.00512 (348/67966). AF 95% confidence interval is 0.00468. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd at 440 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AUTS2NM_015570.4 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/19 ENST00000342771.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AUTS2ENST00000342771.10 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/191 NM_015570.4 P4Q8WXX7-1
AUTS2ENST00000406775.6 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/181 Q8WXX7-2
AUTS2ENST00000403018.3 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/51 Q8WXX7-3
AUTS2ENST00000644939.1 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/19 A1

Frequencies

GnomAD3 genomes
AF:
0.00289
AC:
440
AN:
152036
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000845
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00548
Gnomad EAS
AF:
0.000195
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000660
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00512
Gnomad OTH
AF:
0.00384
GnomAD3 exomes
AF:
0.00341
AC:
38
AN:
11154
Hom.:
1
AF XY:
0.00368
AC XY:
22
AN XY:
5974
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00610
Gnomad ASJ exome
AF:
0.0101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000211
Gnomad NFE exome
AF:
0.00609
Gnomad OTH exome
AF:
0.0155
GnomAD4 exome
AF:
0.00483
AC:
5563
AN:
1152222
Hom.:
22
Cov.:
32
AF XY:
0.00471
AC XY:
2610
AN XY:
554422
show subpopulations
Gnomad4 AFR exome
AF:
0.000990
Gnomad4 AMR exome
AF:
0.00197
Gnomad4 ASJ exome
AF:
0.00533
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000280
Gnomad4 FIN exome
AF:
0.000544
Gnomad4 NFE exome
AF:
0.00546
Gnomad4 OTH exome
AF:
0.00335
GnomAD4 genome
AF:
0.00289
AC:
440
AN:
152146
Hom.:
2
Cov.:
32
AF XY:
0.00238
AC XY:
177
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.000842
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00548
Gnomad4 EAS
AF:
0.000196
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000660
Gnomad4 NFE
AF:
0.00512
Gnomad4 OTH
AF:
0.00380
Alfa
AF:
0.00434
Hom.:
0
Bravo
AF:
0.00296
ExAC
AF:
0.000722
AC:
22
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxNov 28, 2018- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024AUTS2: PP2, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingInvitaeJan 09, 2024- -
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergMar 21, 2023This variant has been identified by standard clinical testing. -
AUTS2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 10, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Intellectual disability Benign:1
Likely benign, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.25
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.76
T;T;T;T
MetaRNN
Benign
0.0038
T;T;T;T
MetaSVM
Benign
-0.83
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.92
D
Polyphen
1.0
.;D;D;.
Vest4
0.38, 0.37, 0.47
MVP
0.47
MPC
2.6
ClinPred
0.067
T
GERP RS
3.6
Varity_R
0.25
gMVP
0.16

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: rs200189077; hg19: chr7-69064650; COSMIC: COSV61410988; COSMIC: COSV61410988; API