3-63912684-GGCA-G

Position:

• chr3-63912684-GGCA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001377405.1(ATXN7):​c.116_118delAGC​(p.Gln39del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00328 in 1,078,090 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 23)
  • Exomes 𝑓: 0.0029 (3 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_deletion
• Clinical Significance: Benign no assertion criteria provided B:2
• Conservation: PhyloP100: 4.60

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 Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BP6: Variant 3-63912684-GGCA-G is Benign according to our data. Variant chr3-63912684-GGCA-G is described in ClinVar as [Benign]. Clinvar id is 1328067.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-63912684-GGCA-G is described in Lovd as [Benign]. Variant chr3-63912684-GGCA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00589 (852/144714) while in subpopulation AFR AF= 0.0169 (676/39996). AF 95% confidence interval is 0.0158. There are 8 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 852 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	3/13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	2/13		NP_001170858.1
ATXN7	NM_000333.4	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	3/13		NP_000324.1
ATXN7	NM_001377406.1	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	2/12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	3/13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 855 AN: 144614 Hom.: 9 Cov.: 23

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00415

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00230

Gnomad SAS AF: 0.00340

Gnomad FIN AF: 0.000118

Gnomad MID AF: 0.00987

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00697

GnomAD3 exomes AF: 0.0230 AC: 238 AN: 10356 Hom.: 0 AF XY: 0.0254 AC XY: 141 AN XY: 5542

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.0588

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.00288 AC: 2689 AN: 933376 Hom.: 3 AF XY: 0.00318 AC XY: 1406 AN XY: 441998

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.00918

Gnomad4 SAS exome AF: 0.00587

Gnomad4 FIN exome AF: 0.00934

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00589 AC: 852 AN: 144714 Hom.: 8 Cov.: 23 AF XY: 0.00582 AC XY: 410 AN XY: 70408

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00415

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00340

Gnomad4 FIN AF: 0.000118

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00690

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs193922929; hg19: chr3-63898360;