3-63987326-A-G

Variant names:

• chr3-63987326-A-G
• rs10510902
• NM_001377405.1:c.1096-733A>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.1096-733A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 152,196 control chromosomes in the GnomAD database, including 202 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 0.046 (202 hom., cov: 32)
• Consequence: ATXN7 NM_001377405.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80
• Publications: 2 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0695 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	NM_001377405.1	MANE Select	c.1096-733A>G		intron	N/A	NP_001364334.1
	ATXN7	NM_001177387.1		c.1096-733A>G		intron	N/A	NP_001170858.1
	ATXN7	NM_000333.4		c.1096-733A>G		intron	N/A	NP_000324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.1096-733A>G		intron	N/A	ENSP00000501377.1
	ATXN7	ENST00000295900.10	TSL:1	c.1096-733A>G		intron	N/A	ENSP00000295900.6
	ATXN7	ENST00000484332.1	TSL:1	c.661-733A>G		intron	N/A	ENSP00000428277.1

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6981 AN: 152078 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.0647

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0431

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

GnomAD4 genome AF: 0.0459 AC: 6992 AN: 152196 Hom.: 202 Cov.: 32 AF XY: 0.0466 AC XY: 3468 AN XY: 74414

African (AFR) AF: 0.0717 AC: 2976 AN: 41534

American (AMR) AF: 0.0364 AC: 556 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4832

European-Finnish (FIN) AF: 0.0647 AC: 685 AN: 10592

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2452 AN: 67996

Other (OTH) AF: 0.0427 AC: 90 AN: 2108

Alfa AF: 0.0396 Hom.: 182

Bravo AF: 0.0449

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.033
DANN	Benign	0.63
PhyloP100		-1.8
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: rs10510902; hg19: chr3-63973002;