3-63912702-A-C

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.104A>C(p.Gln35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,185,296 control chromosomes in the GnomAD database, including 5 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 0.0014 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.496

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=0.011709839).
• BP6: Variant 3-63912702-A-C is Benign according to our data. Variant chr3-63912702-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3057278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-63912702-A-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 207 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN7	NM_001377405.1	c.104A>C	p.Gln35Pro	missense_variant	3/13	ENST00000674280.1
ATXN7	NM_001177387.1	c.104A>C	p.Gln35Pro	missense_variant	2/13
ATXN7	NM_000333.4	c.104A>C	p.Gln35Pro	missense_variant	3/13
ATXN7	NM_001377406.1	c.104A>C	p.Gln35Pro	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN7	ENST00000674280.1	c.104A>C	p.Gln35Pro	missense_variant	3/13		NM_001377405.1	P2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 207 AN: 147518 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000662

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00206

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00246

GnomAD3 exomes AF: 0.000504 AC: 14 AN: 27758 Hom.: 0 AF XY: 0.000388 AC XY: 6 AN XY: 15476

Gnomad AFR exome AF: 0.00417

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.000657

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00234 AC: 2427 AN: 1037676 Hom.: 3 Cov.: 32 AF XY: 0.00224 AC XY: 1113 AN XY: 496300

Gnomad4 AFR exome AF: 0.000297

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.0000580

Gnomad4 SAS exome AF: 0.0000404

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00140 AC: 207 AN: 147620 Hom.: 2 Cov.: 31 AF XY: 0.00117 AC XY: 84 AN XY: 71860

Gnomad4 AFR AF: 0.000660

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00206

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00243

Alfa AF: 0.000433 Hom.: 0

Bravo AF: 0.00179

ExAC AF: 0.0000798 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATXN7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	12
Dann	Benign	0.64
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.27	T;T;T;.;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Pathogenic	0.80	T
Polyphen		0.97, 0.98	.;D;D;D;D
Vest4		0.31, 0.30, 0.31
MVP		0.66
ClinPred		0.031	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.36

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: rs772918244; hg19: chr3-63898378;