rs180696871

Variant names:

• chr3-63999481-C-A
• rs180696871
• NM_001377405.1:c.*14C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001177387.1(ATXN7):​c.2760C>A​(p.Ser920Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,613,846 control chromosomes in the GnomAD database, including 36 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: ATXN7 NM_001177387.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 7

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028598905).
• BP6: Variant 3-63999481-C-A is Benign according to our data. Variant chr3-63999481-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 599471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 610 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177387.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	NM_001377405.1	MANE Select	c.*14C>A		3_prime_UTR	Exon 13 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.2760C>A	p.Ser920Arg	missense	Exon 13 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.*14C>A		3_prime_UTR	Exon 13 of 13	NP_000324.1	O15265-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.*14C>A		3_prime_UTR	Exon 13 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.*14C>A		3_prime_UTR	Exon 13 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000484332.1	TSL:1	c.*14C>A		3_prime_UTR	Exon 9 of 9	ENSP00000428277.1	O15265-3

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152140 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00397 AC: 987 AN: 248820 AF XY: 0.00398

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.00438

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00534

Gnomad NFE exome AF: 0.00606

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00574 AC: 8390 AN: 1461588 Hom.: 34 Cov.: 30 AF XY: 0.00549 AC XY: 3995 AN XY: 727068

African (AFR) AF: 0.00131 AC: 44 AN: 33472

American (AMR) AF: 0.00123 AC: 55 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00227 AC: 196 AN: 86170

European-Finnish (FIN) AF: 0.00532 AC: 284 AN: 53410

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00668 AC: 7422 AN: 1111868

Other (OTH) AF: 0.00450 AC: 272 AN: 60384

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152258 Hom.: 2 Cov.: 31 AF XY: 0.00411 AC XY: 306 AN XY: 74442

African (AFR) AF: 0.000915 AC: 38 AN: 41528

American (AMR) AF: 0.00176 AC: 27 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00530 Hom.: 7

Bravo AF: 0.00380

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00182 AC: 7

ESP6500EA AF: 0.00750 AC: 62

ExAC AF: 0.00388 AC: 469

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ATXN7-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.055
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.37	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.14		Loss of glycosylation at T916 (P = 0.0744)
MVP		0.18
ClinPred		0.023	T
GERP RS		3.3
gMVP		0.028
Mutation Taster		=99/1	polymorphism

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: rs180696871; hg19: chr3-63985157; COSMIC: COSV55756941; COSMIC: COSV55756941;