6-16327384-A-G

Position:

• chr6-16327384-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001128164.2(ATXN1):​c.927T>C​(p.Ala309Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,613,212 control chromosomes in the GnomAD database, including 399,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.73 (40517 hom., cov: 32)
  • Exomes 𝑓: 0.70 (358933 hom.)
• Consequence: ATXN1 NM_001128164.2 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-16327384-A-G is Benign according to our data. Variant chr6-16327384-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128505.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-16327384-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.927T>C	p.Ala309Ala	synonymous_variant	7/8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.927T>C	p.Ala309Ala	synonymous_variant	8/9		NP_000323.2
ATXN1	NM_001357857.2	c.*340T>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.927T>C	p.Ala309Ala	synonymous_variant	7/8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.927T>C	p.Ala309Ala	synonymous_variant	8/9	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110570 AN: 151886 Hom.: 40474 Cov.: 32

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.731 AC: 183269 AN: 250822 Hom.: 67707 AF XY: 0.726 AC XY: 98477 AN XY: 135684

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.860

Gnomad SAS exome AF: 0.773

Gnomad FIN exome AF: 0.669

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.703

GnomAD4 exome AF: 0.699 AC: 1021351 AN: 1461208 Hom.: 358933 Cov.: 117 AF XY: 0.700 AC XY: 508753 AN XY: 726934

Gnomad4 AFR exome AF: 0.793

Gnomad4 AMR exome AF: 0.822

Gnomad4 ASJ exome AF: 0.646

Gnomad4 EAS exome AF: 0.876

Gnomad4 SAS exome AF: 0.769

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.728 AC: 110662 AN: 152004 Hom.: 40517 Cov.: 32 AF XY: 0.731 AC XY: 54280 AN XY: 74282

Gnomad4 AFR AF: 0.793

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.862

Gnomad4 SAS AF: 0.767

Gnomad4 FIN AF: 0.674

Gnomad4 NFE AF: 0.679

Gnomad4 OTH AF: 0.729

Alfa AF: 0.689 Hom.: 15955

Bravo AF: 0.738

EpiCase AF: 0.673

EpiControl AF: 0.667

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
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.8
DANN	Benign	0.27

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: rs179990; hg19: chr6-16327615; COSMIC: COSV55225444; COSMIC: COSV55225444;