6-16306520-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001128164.2(ATXN1):c.2257C>T(p.Pro753Ser) variant causes a missense change. The variant allele was found at a frequency of 0.187 in 1,614,034 control chromosomes in the GnomAD database, including 30,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2367 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28501 hom.)
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.47

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012945831).
• BP6: Variant 6-16306520-G-A is Benign according to our data. Variant chr6-16306520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128499.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-16306520-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.2257C>T	p.Pro753Ser	missense_variant	8/8	ENST00000436367.6
ATXN1	NM_000332.4	c.2257C>T	p.Pro753Ser	missense_variant	9/9
ATXN1	NM_001357857.2	c.*1670C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.2257C>T	p.Pro753Ser	missense_variant	8/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.2257C>T	p.Pro753Ser	missense_variant	9/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23559 AN: 152034 Hom.: 2367 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.177

GnomAD3 exomes AF: 0.195 AC: 48925 AN: 251454 Hom.: 5729 AF XY: 0.195 AC XY: 26550 AN XY: 135902

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.00843

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.190 AC: 278317 AN: 1461882 Hom.: 28501 Cov.: 33 AF XY: 0.191 AC XY: 139000 AN XY: 727244

Gnomad4 AFR exome AF: 0.0311

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.00390

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.155 AC: 23564 AN: 152152 Hom.: 2367 Cov.: 32 AF XY: 0.158 AC XY: 11752 AN XY: 74374

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.00579

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.175

Alfa AF: 0.190 Hom.: 7287

Bravo AF: 0.154

TwinsUK AF: 0.195 AC: 723

ALSPAC AF: 0.200 AC: 771

ESP6500AA AF: 0.0413 AC: 182

ESP6500EA AF: 0.197 AC: 1693

ExAC AF: 0.189 AC: 22911

EpiCase AF: 0.205

EpiControl AF: 0.199

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.11	P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.29	B;B
Vest4		0.10
MPC		1.2
ClinPred		0.013	T
GERP RS		6.1
Varity_R		0.097
gMVP		0.19

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

Other links and lift over

dbSNP: rs16885; hg19: chr6-16306751; COSMIC: COSV104392024;