6-16326641-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001128164.2(ATXN1):ā€‹c.1670T>Cā€‹(p.Val557Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

ATXN1
NM_001128164.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90
Variant links:
Genes affected
ATXN1 (HGNC:10548): (ataxin 1) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15951195).
BS2
High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATXN1NM_001128164.2 linkuse as main transcriptc.1670T>C p.Val557Ala missense_variant 7/8 ENST00000436367.6 NP_001121636.1
ATXN1NM_000332.4 linkuse as main transcriptc.1670T>C p.Val557Ala missense_variant 8/9 NP_000323.2
ATXN1NM_001357857.2 linkuse as main transcriptc.*1083T>C 3_prime_UTR_variant 8/9 NP_001344786.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATXN1ENST00000436367.6 linkuse as main transcriptc.1670T>C p.Val557Ala missense_variant 7/81 NM_001128164.2 ENSP00000416360 P1P54253-1
ATXN1ENST00000244769.8 linkuse as main transcriptc.1670T>C p.Val557Ala missense_variant 8/91 ENSP00000244769 P1P54253-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251056
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.0000617
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461510
Hom.:
0
Cov.:
33
AF XY:
0.0000151
AC XY:
11
AN XY:
727060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.0000243
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 submitterclinical testingAmbry GeneticsJan 19, 2024The c.1670T>C (p.V557A) alteration is located in exon 8 (coding exon 1) of the ATXN1 gene. This alteration results from a T to C substitution at nucleotide position 1670, causing the valine (V) at amino acid position 557 to be replaced by an alanine (A). 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
0.20
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.19
T;T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.57
.;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
0.10
N;N
REVEL
Benign
0.15
Sift
Benign
0.10
T;T
Sift4G
Benign
0.46
T;T
Polyphen
0.0010
B;B
Vest4
0.16
MutPred
0.31
Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP
0.84
MPC
0.50
ClinPred
0.064
T
GERP RS
2.3
Varity_R
0.044
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: rs779004400; hg19: chr6-16326872; API