rs1216716369

Variant names:

• chr3-63912708-A-AGCCGCC
• rs1216716369
• NM_001377405.1:c.112_113insCGCCGC

Your query was ambiguous. Multiple possible variants found:

• chr3-63912708-A-AGCCGCC
• chr3-63912708-A-AGCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001377405.1(ATXN7):​c.112_113insCGCCGC​(p.Gln37_Gln38insProPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,197,694 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• 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: G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 7

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BS2: High AC in GnomAd4 at 9 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.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	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.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.112_113insCGCCGC	p.Gln37_Gln38insProPro	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.0000617 AC: 9 AN: 145848 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000475 AC: 50 AN: 1051742 Hom.: 0 Cov.: 32 AF XY: 0.0000516 AC XY: 26 AN XY: 503888

African (AFR) AF: 0.00 AC: 0 AN: 20190

American (AMR) AF: 0.00 AC: 0 AN: 11144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12668

East Asian (EAS) AF: 0.00 AC: 0 AN: 18568

South Asian (SAS) AF: 0.00175 AC: 45 AN: 25648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 891082

Other (OTH) AF: 0.000127 AC: 5 AN: 39336

GnomAD4 genome AF: 0.0000617 AC: 9 AN: 145952 Hom.: 1 Cov.: 31 AF XY: 0.000112 AC XY: 8 AN XY: 71136

African (AFR) AF: 0.00 AC: 0 AN: 39760

American (AMR) AF: 0.00 AC: 0 AN: 14808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3330

East Asian (EAS) AF: 0.00 AC: 0 AN: 4782

South Asian (SAS) AF: 0.00189 AC: 9 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66258

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spinocerebellar ataxia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.036
Mutation Taster		=73/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1216716369; hg19: chr3-63898384;