chr3-63912635-C-T

Position:

• chr3-63912635-C-T

Variant summary

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

The NM_001377405.1(ATXN7):​c.37C>T​(p.Pro13Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000161 in 1,052,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006052196).
• 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>T	p.Pro13Ser	missense_variant	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.37C>T	p.Pro13Ser	missense_variant	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.37C>T	p.Pro13Ser	missense_variant	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.37C>T	p.Pro13Ser	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>T	p.Pro13Ser	missense_variant	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 41 AN: 148178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00933

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000120

Gnomad OTH AF: 0.000488

GnomAD3 exomes AF: 0.000734 AC: 17 AN: 23168 Hom.: 0 AF XY: 0.000570 AC XY: 8 AN XY: 14024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000143 AC: 129 AN: 904754 Hom.: 1 Cov.: 30 AF XY: 0.000138 AC XY: 59 AN XY: 426774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000365

Gnomad4 ASJ exome AF: 0.00689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000763

Gnomad4 OTH exome AF: 0.000461

GnomAD4 genome AF: 0.000277 AC: 41 AN: 148178 Hom.: 0 Cov.: 32 AF XY: 0.000249 AC XY: 18 AN XY: 72208

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00933

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000120

Gnomad4 OTH AF: 0.000488

ExAC AF: 0.000486 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;.;T;.
Eigen	Benign	-0.028
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.49	T;T;T;T;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0061	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;N;N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.0	D;.;N;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.032	.;.;D;D;D;.
Sift4G	Benign	0.15	.;.;T;T;T;.
Polyphen		0.28, 0.56	.;.;B;P;B;P
Vest4		0.28, 0.26, 0.28
MutPred		0.31		Gain of phosphorylation at P13 (P = 0.0013);Gain of phosphorylation at P13 (P = 0.0013);Gain of phosphorylation at P13 (P = 0.0013);Gain of phosphorylation at P13 (P = 0.0013);Gain of phosphorylation at P13 (P = 0.0013);Gain of phosphorylation at P13 (P = 0.0013);
MVP		0.28
ClinPred		0.17	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
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: rs557445610; hg19: chr3-63898311;