3-63912635-C-G

Position:

• chr3-63912635-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377405.1(ATXN7):​c.37C>G​(p.Pro13Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000522 in 1,053,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084043056).
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.37C>G	p.Pro13Ala	missense_variant	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.37C>G	p.Pro13Ala	missense_variant	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.37C>G	p.Pro13Ala	missense_variant	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.37C>G	p.Pro13Ala	missense_variant	2/12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.37C>G	p.Pro13Ala	missense_variant	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 42 AN: 148178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 14 AN: 904758 Hom.: 0 Cov.: 30 AF XY: 0.0000117 AC XY: 5 AN XY: 426778

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000659

GnomAD4 genome AF: 0.000276 AC: 41 AN: 148286 Hom.: 0 Cov.: 32 AF XY: 0.000318 AC XY: 23 AN XY: 72326

Gnomad4 AFR AF: 0.000974

Gnomad4 AMR AF: 0.0000669

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000246

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The c.37C>G (p.P13A) alteration is located in exon 2 (coding exon 1) of the ATXN7 gene. This alteration results from a C to G substitution at nucleotide position 37, causing the proline (P) at amino acid position 13 to be replaced by an alanine (A). 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	Benign	0.10
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T;.;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.47	T;T;T;T;.;.
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.084	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.0	D;.;N;N;N;.
REVEL	Benign	0.046
Sift	Benign	0.051	.;.;T;D;T;.
Sift4G	Benign	0.23	.;.;T;T;T;.
Polyphen		0.14, 0.34	.;.;B;B;B;B
Vest4		0.26, 0.24
MVP		0.29
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.32

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: rs557445610; hg19: chr3-63898311;