chr3-63912709-G-C

Variant names:

• chr3-63912709-G-C
• rs929040913
• NM_001377405.1:c.111G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377405.1(ATXN7):​c.111G>C​(p.Gln37His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,205,714 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000088 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0360
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081807345).
• BS2: High AC in GnomAd4 at 13 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.111G>C	p.Gln37His	missense	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.111G>C	p.Gln37His	missense	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.111G>C	p.Gln37His	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.111G>C	p.Gln37His	missense	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.111G>C	p.Gln37His	missense	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.111G>C	p.Gln37His	missense	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.0000880 AC: 13 AN: 147808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1057798 Hom.: 0 Cov.: 32 AF XY: 0.00000197 AC XY: 1 AN XY: 506674

⚠️ 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: 20764

American (AMR) AF: 0.00 AC: 0 AN: 11302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12956

East Asian (EAS) AF: 0.00 AC: 0 AN: 18894

South Asian (SAS) AF: 0.00 AC: 0 AN: 25874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 894818

Other (OTH) AF: 0.0000503 AC: 2 AN: 39728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000879 AC: 13 AN: 147916 Hom.: 0 Cov.: 31 AF XY: 0.0000972 AC XY: 7 AN XY: 72032

African (AFR) AF: 0.00 AC: 0 AN: 41032

American (AMR) AF: 0.000804 AC: 12 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4886

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66478

Other (OTH) AF: 0.000485 AC: 1 AN: 2062

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

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	Benign	0.21
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.036
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.043
Sift	Benign	0.13	T
Sift4G	Uncertain	0.049	D
Polyphen		0.14	B
Vest4		0.28
MutPred		0.15		Loss of solvent accessibility (P = 0.1077)
MVP		0.36
ClinPred		0.20	T
GERP RS		1.8
PromoterAI		-0.045	Neutral
Varity_R		0.071
gMVP		0.26
Mutation Taster		=88/12	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: rs929040913; hg19: chr3-63898385;