3-63912714-A-C

Position:

• chr3-63912714-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001377405.1(ATXN7):​c.116A>C​(p.Gln39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,212,584 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012874275).
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.116A>C	p.Gln39Pro	missense_variant	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.116A>C	p.Gln39Pro	missense_variant	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.116A>C	p.Gln39Pro	missense_variant	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.116A>C	p.Gln39Pro	missense_variant	2/12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.116A>C	p.Gln39Pro	missense_variant	3/13		NM_001377405.1	ENSP00000501377	P2

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 43 AN: 146898 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.00336

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.000935 AC: 30 AN: 32074 Hom.: 0 AF XY: 0.000938 AC XY: 17 AN XY: 18122

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.000567

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.000426 AC: 454 AN: 1065578 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 234 AN XY: 510578

Gnomad4 AFR exome AF: 0.000526

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.000527

Gnomad4 EAS exome AF: 0.00167

Gnomad4 SAS exome AF: 0.00162

Gnomad4 FIN exome AF: 0.000190

Gnomad4 NFE exome AF: 0.000345

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000293 AC: 43 AN: 147006 Hom.: 1 Cov.: 31 AF XY: 0.000377 AC XY: 27 AN XY: 71544

Gnomad4 AFR AF: 0.000223

Gnomad4 AMR AF: 0.000202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000416

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000181

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000211 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.63
DEOGEN2	Benign	0.10	.;T;.;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.20	T;T;T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.43	.;N;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.35	.;T;T;T;.
Sift4G	Benign	0.094	.;T;T;T;.
Vest4		0.25, 0.24, 0.28
MVP		0.19
ClinPred		0.0080	T
Varity_R		0.15
gMVP		0.26

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: rs868854400; hg19: chr3-63898390; COSMIC: COSV55749379; COSMIC: COSV55749379;