rs2241821

Positions:

• chr3-63990469-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377405.1(ATXN7):​c.1560+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,459,308 control chromosomes in the GnomAD database, including 5,535 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.069 (466 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5069 hom.)
• Consequence: ATXN7 NM_001377405.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

Genes affected

ATXN7 (HGNC:10560): (ataxin 7) 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. This locus has been mapped to chromosome 3, and it has been determined that the diseased allele associated with spinocerebellar ataxia-7 contains 37-306 CAG repeats (near the N-terminus), compared to 4-35 in the normal allele. The encoded protein is a component of the SPT3/TAF9/GCN5 acetyltransferase (STAGA) and TBP-free TAF-containing (TFTC) chromatin remodeling complexes, and it thus plays a role in transcriptional regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.1560+95G>A		intron_variant		ENST00000674280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.1560+95G>A		intron_variant			NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10546 AN: 152184 Hom.: 465 Cov.: 32

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0864

GnomAD4 exome AF: 0.0843 AC: 110129 AN: 1307006 Hom.: 5069 Cov.: 20 AF XY: 0.0842 AC XY: 54786 AN XY: 650832

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.0996

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.0943

Gnomad4 FIN exome AF: 0.0493

Gnomad4 NFE exome AF: 0.0811

Gnomad4 OTH exome AF: 0.0847

GnomAD4 genome AF: 0.0693 AC: 10551 AN: 152302 Hom.: 466 Cov.: 32 AF XY: 0.0688 AC XY: 5121 AN XY: 74466

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.0946

Gnomad4 FIN AF: 0.0485

Gnomad4 NFE AF: 0.0804

Gnomad4 OTH AF: 0.0855

Alfa AF: 0.0869 Hom.: 686

Bravo AF: 0.0754

Asia WGS AF: 0.0880 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0080
DANN	Benign	0.81

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: rs2241821; hg19: chr3-63976145;