3-63912635-C-T

Variant names:

• chr3-63912635-C-T
• rs557445610
• NM_001377405.1:c.37C>T

Variant summary

Our verdict is Benign. The variant received -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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13A) has been classified 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
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006052196).
• BS2: High AC in GnomAd4 at 41 AD gene.

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.37C>T	p.Pro13Ser	missense	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.37C>T	p.Pro13Ser	missense	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.37C>T	p.Pro13Ser	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.37C>T	p.Pro13Ser	missense	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.37C>T	p.Pro13Ser	missense	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000474513.6	TSL:1	c.37C>T	p.Pro13Ser	missense	Exon 4 of 4	ENSP00000418203.2	A0A1B0GX67

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

GnomAD2 exomes AF: 0.000734 AC: 17 AN: 23168 AF XY: 0.000570

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 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

African (AFR) AF: 0.00 AC: 0 AN: 16722

American (AMR) AF: 0.000365 AC: 1 AN: 2740

Ashkenazi Jewish (ASJ) AF: 0.00689 AC: 53 AN: 7690

East Asian (EAS) AF: 0.00 AC: 0 AN: 5614

South Asian (SAS) AF: 0.00 AC: 0 AN: 23020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1898

European-Non Finnish (NFE) AF: 0.0000763 AC: 61 AN: 799220

Other (OTH) AF: 0.000461 AC: 14 AN: 30340

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

African (AFR) AF: 0.00 AC: 0 AN: 40936

American (AMR) AF: 0.00 AC: 0 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00933 AC: 32 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000120 AC: 8 AN: 66730

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000486 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.028
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.042
Sift	Benign	0.032	D
Sift4G	Benign	0.15	T
Polyphen		0.28	B
Vest4		0.28
MutPred		0.31		Gain of phosphorylation at P13 (P = 0.0013)
MVP		0.28
ClinPred		0.17	T
GERP RS		3.8
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.36
Mutation Taster		=83/17	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: rs557445610; hg19: chr3-63898311;