7-69599771-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PM2_SupportingBP4_Moderate

The NM_015570(AUTS2):c.118G>A(p.Ala40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 151794 control chromosomes in the gnomAD Genomes 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: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

AUTS2
NM_015570 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.550

Links

AUTS2 (HGNC:14262):

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.0000264 (4/151794) while in subpopulation NFE AF= 0.0000589 (4/67896). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in gnomad. There are 1 alleles in male gnomad subpopulation. Median coverage is 32. This position pass quality control queck.

BP4

Computational evidence support a benign effect (MetaRNN=0.0892635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUTS2	NM_015570.4 linkuse as main transcript	c.118G>A	p.Ala40Thr	missense_variant	1/19	ENST00000342771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUTS2	ENST00000342771.10 linkuse as main transcript	c.118G>A	p.Ala40Thr	missense_variant	1/19	1	NM_015570.4	P4	Q8WXX7-1
AUTS2	ENST00000406775.6 linkuse as main transcript	c.118G>A	p.Ala40Thr	missense_variant	1/18	1			Q8WXX7-2
AUTS2	ENST00000403018.3 linkuse as main transcript	c.118G>A	p.Ala40Thr	missense_variant	1/5	1			Q8WXX7-3
AUTS2	ENST00000644939.1 linkuse as main transcript	c.118G>A	p.Ala40Thr	missense_variant	1/19			A1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000217

AC:

AN:

92074

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000609

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1326420

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

653552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000369

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:

0.0000134

Gnomad4 OTH exome

AF:

0.0000367

Alfa

AF:

0.0000587

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2016

The A40T variant in the AUTS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 4400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A40T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved mammals. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret A40T as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.64

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.54

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.089

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.86

Polyphen

0.0

.;B;B;.

Vest4

0.12, 0.10, 0.14

MutPred

0.29

Gain of phosphorylation at A40 (P = 0.0321);Gain of phosphorylation at A40 (P = 0.0321);Gain of phosphorylation at A40 (P = 0.0321);Gain of phosphorylation at A40 (P = 0.0321);

MVP

0.10

MPC

1.5

ClinPred

0.19

GERP RS

1.7

Varity_R

0.072

gMVP

0.059

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over