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12-6935780-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001940.4(ATN1):c.513G>A(p.Pro171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,612,506 control chromosomes in the GnomAD database, including 394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 62 hom., cov: 31)
Exomes 𝑓: 0.0041 ( 332 hom. )

Consequence

ATN1
NM_001940.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.78
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-6935780-G-A is Benign according to our data. Variant chr12-6935780-G-A is described in ClinVar as [Benign]. Clinvar id is 1304826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-4.78 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATN1NM_001940.4 linkuse as main transcriptc.513G>A p.Pro171= synonymous_variant 5/10 ENST00000396684.3
ATN1NM_001007026.2 linkuse as main transcriptc.513G>A p.Pro171= synonymous_variant 5/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATN1ENST00000396684.3 linkuse as main transcriptc.513G>A p.Pro171= synonymous_variant 5/101 NM_001940.4 P1
ATN1ENST00000356654.8 linkuse as main transcriptc.513G>A p.Pro171= synonymous_variant 5/101 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00859
AC:
1297
AN:
151050
Hom.:
60
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0705
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0194
Gnomad SAS
AF:
0.000419
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.0149
GnomAD3 exomes
AF:
0.0184
AC:
4602
AN:
250136
Hom.:
283
AF XY:
0.0136
AC XY:
1837
AN XY:
135286
show subpopulations
Gnomad AFR exome
AF:
0.00148
Gnomad AMR exome
AF:
0.119
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0204
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000213
Gnomad OTH exome
AF:
0.0136
GnomAD4 exome
AF:
0.00408
AC:
5957
AN:
1461340
Hom.:
332
Cov.:
38
AF XY:
0.00339
AC XY:
2465
AN XY:
726972
show subpopulations
Gnomad4 AFR exome
AF:
0.00111
Gnomad4 AMR exome
AF:
0.110
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0174
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000666
Gnomad4 OTH exome
AF:
0.00391
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00863
AC:
1305
AN:
151166
Hom.:
62
Cov.:
31
AF XY:
0.00971
AC XY:
717
AN XY:
73838
show subpopulations
Gnomad4 AFR
AF:
0.00192
Gnomad4 AMR
AF:
0.0710
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0195
Gnomad4 SAS
AF:
0.000420
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.0147
Alfa
AF:
0.00105
Hom.:
1
Bravo
AF:
0.0145
Asia WGS
AF:
0.00779
AC:
27
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJul 22, 2021- -
ATN1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 20, 2020This variant is classified as 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
BayesDel_noAF
Benign
-0.79
Cadd
Benign
0.027
Dann
Benign
0.83
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs144111044; hg19: chr12-7044943; API