chr3-63912677-G-A

Variant names:

• chr3-63912677-G-A
• rs2107296199
• NM_001377405.1:c.79G>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.79G>A​(p.Ala27Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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=0.24539644).

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.79G>A	p.Ala27Thr	missense	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.79G>A	p.Ala27Thr	missense	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.79G>A	p.Ala27Thr	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.79G>A	p.Ala27Thr	missense	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.79G>A	p.Ala27Thr	missense	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.79G>A	p.Ala27Thr	missense	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000225 AC: 2 AN: 887596 Hom.: 0 Cov.: 30 AF XY: 0.00000478 AC XY: 2 AN XY: 418666

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17084

American (AMR) AF: 0.00 AC: 0 AN: 3438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6868

East Asian (EAS) AF: 0.00 AC: 0 AN: 7428

South Asian (SAS) AF: 0.00 AC: 0 AN: 18196

European-Finnish (FIN) AF: 0.0000617 AC: 1 AN: 16202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1940

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 785898

Other (OTH) AF: 0.00 AC: 0 AN: 30542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.35
MutPred		0.26		Gain of phosphorylation at A27 (P = 0.0331)
MVP		0.41
ClinPred		0.89	D
GERP RS		3.7
PromoterAI		0.0078	Neutral
Varity_R		0.10
gMVP		0.39
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: rs2107296199; hg19: chr3-63898353;