12-6935548-A-G

Position:

chr12-6935548-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_001424179.1(ATN1):c.280-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000373 in 1,607,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATN1
NM_001424179.1 splice_acceptor, intron

Scores

Splicing: ADA: 0.01414

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.68

Variant links:

Genes affected

ATN1 (HGNC:3033): (atrophin 1) Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

ATN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5633053 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.2, offset of -3, new splice context is: gagtcttcccttttctacAGcgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATN1	NM_001940.4 linkuse as main transcript	c.281A>G	p.Gln94Arg	missense_variant, splice_region_variant	5/10	ENST00000396684.3	NP_001931.2	P54259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3 linkuse as main transcript	c.281A>G	p.Gln94Arg	missense_variant, splice_region_variant	5/10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 linkuse as main transcript	c.281A>G	p.Gln94Arg	missense_variant, splice_region_variant	5/10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248740

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1455242

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The c.281A>G (p.Q94R) alteration is located in exon 5 (coding exon 4) of the ATN1 gene. This alteration results from a A to G substitution at nucleotide position 281, causing the glutamine (Q) at amino acid position 94 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.56

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.16

Sift

Benign

0.059

T;T

Sift4G

Benign

0.085

T;T

Polyphen

0.99

D;D

Vest4

0.40

MutPred

0.30

Gain of catalytic residue at L96 (P = 0.0048);Gain of catalytic residue at L96 (P = 0.0048);

MVP

0.52

MPC

0.32

ClinPred

0.46

GERP RS

4.0

Varity_R

0.16

gMVP

0.058

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.014

dbscSNV1_RF

Benign

0.046

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over