rs3774729

Variant names:

• chr3-63996406-G-A
• rs3774729
• NM_001377405.1:c.2584G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-63996406-G-A
• chr3-63996406-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (13143 hom., cov: 31)
  • Exomes 𝑓: 0.32 (78121 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.264
• Publications: 43 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 -14 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 Benign. ClinVar VariationId is 128518.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 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.2584G>A	p.Val862Met	missense	Exon 12 of 13	NP_001364334.1
	ATXN7	NM_001177387.1		c.2584G>A	p.Val862Met	missense	Exon 11 of 13	NP_001170858.1
	ATXN7	NM_000333.4		c.2584G>A	p.Val862Met	missense	Exon 12 of 13	NP_000324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.2584G>A	p.Val862Met	missense	Exon 12 of 13	ENSP00000501377.1
	ATXN7	ENST00000295900.10	TSL:1	c.2584G>A	p.Val862Met	missense	Exon 12 of 13	ENSP00000295900.6
	ATXN7	ENST00000484332.1	TSL:1	c.2149G>A	p.Val717Met	missense	Exon 8 of 9	ENSP00000428277.1

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

GnomAD2 exomes AF: 0.344 AC: 85844 AN: 249242 AF XY: 0.339

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 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

African (AFR) AF: 0.587 AC: 19664 AN: 33480

American (AMR) AF: 0.301 AC: 13482 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 10427 AN: 26136

East Asian (EAS) AF: 0.478 AC: 18971 AN: 39700

South Asian (SAS) AF: 0.298 AC: 25715 AN: 86258

European-Finnish (FIN) AF: 0.322 AC: 17225 AN: 53418

Middle Eastern (MID) AF: 0.337 AC: 1945 AN: 5768

European-Non Finnish (NFE) AF: 0.308 AC: 342115 AN: 1111992

Other (OTH) AF: 0.351 AC: 21204 AN: 60396

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

African (AFR) AF: 0.578 AC: 23944 AN: 41404

American (AMR) AF: 0.332 AC: 5065 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1429 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2467 AN: 5126

South Asian (SAS) AF: 0.289 AC: 1396 AN: 4834

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10564

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21523 AN: 67948

Other (OTH) AF: 0.404 AC: 853 AN: 2112

Alfa AF: 0.343 Hom.: 36826

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000037	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.79	N
PhyloP100		-0.26
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.074
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0050	B
Vest4		0.032
ClinPred		0.0012	T
GERP RS		-1.6
Varity_R		0.017
gMVP		0.057
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: rs3774729; hg19: chr3-63982082; COSMIC: COSV55751053; COSMIC: COSV55751053;