chr3-63912654-C-A

Variant names:

• chr3-63912654-C-A
• rs2107296086
• NM_001377405.1:c.56C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377405.1(ATXN7):​c.56C>A​(p.Ala19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000112 in 889,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17941487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.56C>A	p.Ala19Glu	missense_variant	Exon 3 of 13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.56C>A	p.Ala19Glu	missense_variant	Exon 2 of 13		NP_001170858.1
ATXN7	NM_000333.4	c.56C>A	p.Ala19Glu	missense_variant	Exon 3 of 13		NP_000324.1
ATXN7	NM_001377406.1	c.56C>A	p.Ala19Glu	missense_variant	Exon 2 of 12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.56C>A	p.Ala19Glu	missense_variant	Exon 3 of 13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 889040 Hom.: 0 Cov.: 30 AF XY: 0.00000240 AC XY: 1 AN XY: 416968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16650

American (AMR) AF: 0.00 AC: 0 AN: 2302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6218

East Asian (EAS) AF: 0.00 AC: 0 AN: 5488

South Asian (SAS) AF: 0.00 AC: 0 AN: 18506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1840

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 793504

Other (OTH) AF: 0.00 AC: 0 AN: 29806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>A (p.A19E) alteration is located in exon 2 (coding exon 1) of the ATXN7 gene. This alteration results from a C to A substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.11	.;.;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.42	T;T;T;T;.;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;N;N;N;N
PhyloP100		3.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;.;N;N;N;.
REVEL	Benign	0.092
Sift	Benign	0.049	.;.;D;D;D;.
Sift4G	Uncertain	0.056	.;.;T;D;T;.
Polyphen		0.94, 0.97	.;.;P;D;P;D
Vest4		0.48, 0.46, 0.48
MutPred		0.36		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.36
ClinPred		0.50	D
GERP RS		1.9
PromoterAI		0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.49
Mutation Taster		=89/11	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: rs2107296086; hg19: chr3-63898330;