6-16326641-A-G
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001128164.2(ATXN1):āc.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
NM_001128164.2 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 3.90
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]
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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 |
---|---|---|---|---|---|---|---|---|
ATXN1 | NM_001128164.2 | c.1670T>C | p.Val557Ala | missense_variant | 7/8 | ENST00000436367.6 | NP_001121636.1 | |
ATXN1 | NM_000332.4 | c.1670T>C | p.Val557Ala | missense_variant | 8/9 | NP_000323.2 | ||
ATXN1 | NM_001357857.2 | c.*1083T>C | 3_prime_UTR_variant | 8/9 | NP_001344786.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATXN1 | ENST00000436367.6 | c.1670T>C | p.Val557Ala | missense_variant | 7/8 | 1 | NM_001128164.2 | ENSP00000416360 | P1 | |
ATXN1 | ENST00000244769.8 | c.1670T>C | p.Val557Ala | missense_variant | 8/9 | 1 | ENSP00000244769 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251056Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135742
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461510Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727060
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
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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 | Jan 19, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at