3-63912714-A-C

Variant names:

• chr3-63912714-A-C
• rs868854400
• NM_001377405.1:c.116A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001377405.1(ATXN7):​c.116A>C​(p.Gln39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,212,584 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00
• Publications: 3 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=0.012874275).
• BS2: High AC in GnomAd4 at 43 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.116A>C	p.Gln39Pro	missense	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.116A>C	p.Gln39Pro	missense	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.116A>C	p.Gln39Pro	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.116A>C	p.Gln39Pro	missense	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.116A>C	p.Gln39Pro	missense	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.116A>C	p.Gln39Pro	missense	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 43 AN: 146898 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.00336

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.000494

GnomAD2 exomes AF: 0.000935 AC: 30 AN: 32074 AF XY: 0.000938

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000567

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.000426 AC: 454 AN: 1065578 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 234 AN XY: 510578

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

African (AFR) AF: 0.000526 AC: 11 AN: 20928

American (AMR) AF: 0.000873 AC: 10 AN: 11450

Ashkenazi Jewish (ASJ) AF: 0.000527 AC: 7 AN: 13276

East Asian (EAS) AF: 0.00167 AC: 33 AN: 19742

South Asian (SAS) AF: 0.00162 AC: 42 AN: 25968

European-Finnish (FIN) AF: 0.000190 AC: 6 AN: 31604

Middle Eastern (MID) AF: 0.00258 AC: 7 AN: 2712

European-Non Finnish (NFE) AF: 0.000345 AC: 310 AN: 899610

Other (OTH) AF: 0.000695 AC: 28 AN: 40288

⚠️ 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: 0.000293 AC: 43 AN: 147006 Hom.: 1 Cov.: 31 AF XY: 0.000377 AC XY: 27 AN XY: 71544

African (AFR) AF: 0.000223 AC: 9 AN: 40426

American (AMR) AF: 0.000202 AC: 3 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.000416 AC: 2 AN: 4806

South Asian (SAS) AF: 0.00336 AC: 16 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9136

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

European-Non Finnish (NFE) AF: 0.000181 AC: 12 AN: 66358

Other (OTH) AF: 0.000488 AC: 1 AN: 2048

Alfa AF: 0.000211 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.63
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.042
Sift	Benign	0.35	T
Sift4G	Benign	0.094	T
Vest4		0.25
MVP		0.19
ClinPred		0.0080	T
PromoterAI		0.00040	Neutral
Varity_R		0.15
gMVP		0.26
Mutation Taster		=92/8	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: rs868854400; hg19: chr3-63898390; COSMIC: COSV55749379; COSMIC: COSV55749379;