rs2241822

Variant names:

• chr3-63979628-A-G
• rs2241822
• NM_001377405.1:c.500-287A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377405.1(ATXN7):​c.500-287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,162 control chromosomes in the GnomAD database, including 1,032 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 0.10 (1032 hom., cov: 32)
• Consequence: ATXN7 NM_001377405.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 5 publications found

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]

ATXN7 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• spinocerebellar ataxia type 7

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.500-287A>G		intron_variant	Intron 5 of 12	ENST00000674280.1	NP_001364334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.500-287A>G		intron_variant	Intron 5 of 12		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15848 AN: 152044 Hom.: 1031 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.131

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.104 AC: 15851 AN: 152162 Hom.: 1032 Cov.: 32 AF XY: 0.102 AC XY: 7618 AN XY: 74392

African (AFR) AF: 0.0362 AC: 1503 AN: 41562

American (AMR) AF: 0.155 AC: 2376 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3472

East Asian (EAS) AF: 0.141 AC: 726 AN: 5144

South Asian (SAS) AF: 0.121 AC: 581 AN: 4814

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10598

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9054 AN: 67980

Other (OTH) AF: 0.129 AC: 272 AN: 2106

Alfa AF: 0.127 Hom.: 586

Bravo AF: 0.111

Asia WGS AF: 0.103 AC: 360 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	0.14
DANN	Benign	0.50
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2241822; hg19: chr3-63965304;