3-63912809-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001377405.1(ATXN7):c.211T>G(p.Ser71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,564,862 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.954

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006044239).
• BP6: Variant 3-63912809-T-G is Benign according to our data. Variant chr3-63912809-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 208954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.211T>G	p.Ser71Ala	missense_variant	3/13	ENST00000674280.1
ATXN7	NM_001177387.1	c.211T>G	p.Ser71Ala	missense_variant	2/13
ATXN7	NM_000333.4	c.211T>G	p.Ser71Ala	missense_variant	3/13
ATXN7	NM_001377406.1	c.211T>G	p.Ser71Ala	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.211T>G	p.Ser71Ala	missense_variant	3/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.000469 AC: 71 AN: 151276 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.0177

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000586 AC: 117 AN: 199606 Hom.: 0 AF XY: 0.000588 AC XY: 66 AN XY: 112162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.000357 AC: 504 AN: 1413586 Hom.: 3 Cov.: 33 AF XY: 0.000351 AC XY: 247 AN XY: 703216

Gnomad4 AFR exome AF: 0.000103

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.000469 AC: 71 AN: 151276 Hom.: 0 Cov.: 31 AF XY: 0.000393 AC XY: 29 AN XY: 73814

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.0177

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000484

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000984 AC: 8

ExAC AF: 0.000508 AC: 61

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

ATXN7: BS1 -

Abnormality of neuronal migration Benign:1

Benign, no assertion criteria provided

clinical testing

Génétique et pathophysiologie de maladies neurodéveloppementales et épileptogènes, Institut de génétique et de biologie moléculaire et cellulaire

Oct 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.30	T;T;T;.;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0060	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Pathogenic	0.87	D
Polyphen		0.0010	.;B;B;B;B
Vest4		0.17, 0.18, 0.18
MVP		0.32
ClinPred		0.060	T
GERP RS		1.1
Varity_R		0.097
gMVP		0.14

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: rs201561286; hg19: chr3-63898485; COSMIC: COSV105160148; COSMIC: COSV105160148;