rs3774729

chr3-63996406-G-Achr3-63996406-G-T

Variant summary

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

The NM_001377405.1(ATXN7):c.2584G>A(p.Val862Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,796 control chromosomes in the GnomAD database, including 91,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.40 (13143 hom., cov: 31)
  • Exomes 𝑓: 0.32 (78121 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.264

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7316197E-5).
• BP6: Variant 3-63996406-G-A is Benign according to our data. Variant chr3-63996406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128518.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.2584G>A	p.Val862Met	missense_variant	12/13	ENST00000674280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.2584G>A	p.Val862Met	missense_variant	12/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60465 AN: 151806 Hom.: 13114 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.404

GnomAD3 exomes AF: 0.344 AC: 85844 AN: 249242 Hom.: 15608 AF XY: 0.339 AC XY: 45894 AN XY: 135306

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.495

Gnomad SAS exome AF: 0.299

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.322 AC: 470748 AN: 1461872 Hom.: 78121 Cov.: 53 AF XY: 0.321 AC XY: 233722 AN XY: 727234

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.399

Gnomad4 EAS exome AF: 0.478

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.399 AC: 60542 AN: 151924 Hom.: 13143 Cov.: 31 AF XY: 0.396 AC XY: 29409 AN XY: 74252

Gnomad4 AFR AF: 0.578

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.404

Alfa AF: 0.327 Hom.: 21714

Bravo AF: 0.409

TwinsUK AF: 0.294 AC: 1089

ALSPAC AF: 0.309 AC: 1190

ESP6500AA AF: 0.558 AC: 2374

ESP6500EA AF: 0.307 AC: 2612

ExAC AF: 0.347 AC: 42058

Asia WGS AF: 0.422 AC: 1468 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.312

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	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	3.5
Dann	Benign	0.17
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T;T;T;.;.;T
MetaRNN	Benign	0.000037	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.34	T
Polyphen		0.0050, 0.028	.;B;B;B;B;.
Vest4		0.032, 0.035, 0.071
ClinPred		0.0012	T
GERP RS		-1.6
Varity_R		0.017
gMVP		0.057

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: rs3774729; hg19: chr3-63982082; COSMIC: COSV55751053; COSMIC: COSV55751053;