NM_001377405.1:c.179C>A

Variant names:

• chr3-63912777-C-A
• rs755508121
• NM_001377405.1:c.179C>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.179C>A​(p.Pro60Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000297 in 1,348,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P60R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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: G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 7

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

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=0.15034097).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	NM_001377405.1	MANE Select	c.179C>A	p.Pro60Gln	missense	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.179C>A	p.Pro60Gln	missense	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.179C>A	p.Pro60Gln	missense	Exon 3 of 13	NP_000324.1	O15265-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7	ENST00000674280.1	MANE Select	c.179C>A	p.Pro60Gln	missense	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.179C>A	p.Pro60Gln	missense	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.179C>A	p.Pro60Gln	missense	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000297 AC: 4 AN: 1348040 Hom.: 0 Cov.: 33 AF XY: 0.00000299 AC XY: 2 AN XY: 668412

African (AFR) AF: 0.00 AC: 0 AN: 27200

American (AMR) AF: 0.00 AC: 0 AN: 27040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21714

East Asian (EAS) AF: 0.00 AC: 0 AN: 31020

South Asian (SAS) AF: 0.00 AC: 0 AN: 73170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4918

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1059448

Other (OTH) AF: 0.0000182 AC: 1 AN: 54914

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.15	T
Polyphen		0.84	P
Vest4		0.26
MutPred		0.10		Loss of catalytic residue at P60 (P = 0.0716)
MVP		0.26
ClinPred		0.58	D
GERP RS		3.7
PromoterAI		0.0046	Neutral
Varity_R		0.14
gMVP		0.32
Mutation Taster		=91/9	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: rs755508121; hg19: chr3-63898453;