chr3-63912714-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377405.1(ATXN7):​c.116A>G​(p.Gln39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,212,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07503754).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.116A>G	p.Gln39Arg	missense_variant	Exon 3 of 13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.116A>G	p.Gln39Arg	missense_variant	Exon 2 of 13		NP_001170858.1
ATXN7	NM_000333.4	c.116A>G	p.Gln39Arg	missense_variant	Exon 3 of 13		NP_000324.1
ATXN7	NM_001377406.1	c.116A>G	p.Gln39Arg	missense_variant	Exon 2 of 12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.116A>G	p.Gln39Arg	missense_variant	Exon 3 of 13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.0000340 AC: 5 AN: 146902 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000622

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000494

GnomAD4 exome AF: 0.00000469 AC: 5 AN: 1065666 Hom.: 0 Cov.: 32 AF XY: 0.00000588 AC XY: 3 AN XY: 510618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000340 AC: 5 AN: 147010 Hom.: 0 Cov.: 31 AF XY: 0.0000280 AC XY: 2 AN XY: 71548

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000624

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000488

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.4
DANN	Benign	0.43
DEOGEN2	Benign	0.093	.;T;.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.19	T;T;T;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.075	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	.;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.23	.;N;N;N;.
REVEL	Benign	0.050
Sift	Benign	0.93	.;T;T;T;.
Sift4G	Benign	1.0	.;T;T;T;.
Vest4		0.19, 0.18, 0.20
MutPred		0.23		Gain of MoRF binding (P = 0.0783);Gain of MoRF binding (P = 0.0783);Gain of MoRF binding (P = 0.0783);Gain of MoRF binding (P = 0.0783);Gain of MoRF binding (P = 0.0783);
MVP		0.16
ClinPred		0.068	T
Varity_R		0.15
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs868854400; hg19: chr3-63898390;