3-63912693-A-C

Position:

• chr3-63912693-A-C

Variant summary

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

The NM_001377405.1(ATXN7):​c.95A>C​(p.Gln32Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,128,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.563

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=0.08769816).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.95A>C	p.Gln32Pro	missense_variant	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.95A>C	p.Gln32Pro	missense_variant	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.95A>C	p.Gln32Pro	missense_variant	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.95A>C	p.Gln32Pro	missense_variant	2/12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.95A>C	p.Gln32Pro	missense_variant	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.0000282 AC: 4 AN: 141808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000308

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 13 AN: 986416 Hom.: 0 Cov.: 32 AF XY: 0.0000128 AC XY: 6 AN XY: 470564

Gnomad4 AFR exome AF: 0.000165

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000876

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000588

Gnomad4 OTH exome AF: 0.0000836

GnomAD4 genome AF: 0.0000282 AC: 4 AN: 141808 Hom.: 0 Cov.: 31 AF XY: 0.0000435 AC XY: 3 AN XY: 69036

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000212

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000308

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

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

Sep 25, 2024

The c.95A>C (p.Q32P) alteration is located in exon 2 (coding exon 1) of the ATXN7 gene. This alteration results from a A to C substitution at nucleotide position 95, causing the glutamine (Q) at amino acid position 32 to be replaced by a proline (P). 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	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.43
DEOGEN2	Benign	0.13	.;T;.;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.45	T;T;T;.;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.088	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N;N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.43	.;N;N;N;.
REVEL	Benign	0.087
Sift	Benign	0.38	.;T;T;T;.
Sift4G	Benign	0.13	.;T;T;T;.
Polyphen		0.60, 0.72	.;P;P;P;P
Vest4		0.36, 0.39, 0.35
MutPred		0.18		Gain of glycosylation at Q32 (P = 0.0132);Gain of glycosylation at Q32 (P = 0.0132);Gain of glycosylation at Q32 (P = 0.0132);Gain of glycosylation at Q32 (P = 0.0132);Gain of glycosylation at Q32 (P = 0.0132);
MVP		0.69
ClinPred		0.18	T
GERP RS		0.23
Varity_R		0.086
gMVP		0.34

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: rs986062347; hg19: chr3-63898369;