3-63912714-A-AGCAGCAGCC

Variant names:

• chr3-63912714-A-AGCAGCAGCC
• rs770364745
• NM_001377405.1:c.118_119insAGCAGCCGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001377405.1(ATXN7):​c.118_119insAGCAGCCGC​(p.Gln39_Pro40insGlnGlnPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 146,964 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0065 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.825

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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BS2: High AC in GnomAd4 at 948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7	NM_001377405.1	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENST00000674280.1	NP_001364334.1
ATXN7	NM_001177387.1	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 2 of 13		NP_001170858.1
ATXN7	NM_000333.4	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13		NP_000324.1
ATXN7	NM_001377406.1	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 2 of 12		NP_001364335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7	ENST00000674280.1	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13		NM_001377405.1	ENSP00000501377.1

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 943 AN: 146860 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00781

Gnomad ASJ AF: 0.00767

Gnomad EAS AF: 0.000830

Gnomad SAS AF: 0.00651

Gnomad FIN AF: 0.00241

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00938

GnomAD3 exomes AF: 0.000655 AC: 21 AN: 32074 Hom.: 0 AF XY: 0.000607 AC XY: 11 AN XY: 18122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000568

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000187

Gnomad FIN exome AF: 0.00132

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00303 AC: 3229 AN: 1064670 Hom.: 8 Cov.: 32 AF XY: 0.00298 AC XY: 1521 AN XY: 510154

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00157

Gnomad4 SAS exome AF: 0.00702

Gnomad4 FIN exome AF: 0.00108

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00645 AC: 948 AN: 146964 Hom.: 2 Cov.: 31 AF XY: 0.00629 AC XY: 450 AN XY: 71528

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00780

Gnomad4 ASJ AF: 0.00767

Gnomad4 EAS AF: 0.000832

Gnomad4 SAS AF: 0.00652

Gnomad4 FIN AF: 0.00241

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0103

Alfa AF: 0.000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770364745; hg19: chr3-63898390;