3-63912714-AGCC-AGCCGCCGCC

Variant names:

• chr3-63912714-A-AGCCGCC
• rs1553686135
• NM_001377405.1:c.120_125dupGCCGCC

Variant summary

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

The NM_001377405.1(ATXN7):​c.120_125dupGCCGCC​(p.Pro41_Pro42dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,212,670 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.825
• 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 51 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.120_125dupGCCGCC	p.Pro41_Pro42dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.120_125dupGCCGCC	p.Pro41_Pro42dup	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.120_125dupGCCGCC	p.Pro41_Pro42dup	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.120_125dupGCCGCC	p.Pro41_Pro42dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.120_125dupGCCGCC	p.Pro41_Pro42dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.120_125dupGCCGCC	p.Pro41_Pro42dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 52 AN: 146902 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000125 AC: 4 AN: 32074 AF XY: 0.000166

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000610 AC: 65 AN: 1065660 Hom.: 0 Cov.: 32 AF XY: 0.0000783 AC XY: 40 AN XY: 510614

African (AFR) AF: 0.000382 AC: 8 AN: 20934

American (AMR) AF: 0.00245 AC: 28 AN: 11446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13278

East Asian (EAS) AF: 0.0000506 AC: 1 AN: 19748

South Asian (SAS) AF: 0.000154 AC: 4 AN: 25970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31604

Middle Eastern (MID) AF: 0.000368 AC: 1 AN: 2714

European-Non Finnish (NFE) AF: 0.0000222 AC: 20 AN: 899676

Other (OTH) AF: 0.0000745 AC: 3 AN: 40290

GnomAD4 genome AF: 0.000347 AC: 51 AN: 147010 Hom.: 0 Cov.: 31 AF XY: 0.000307 AC XY: 22 AN XY: 71548

African (AFR) AF: 0.0000742 AC: 3 AN: 40428

American (AMR) AF: 0.00282 AC: 42 AN: 14886

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

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4808

South Asian (SAS) AF: 0.000210 AC: 1 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: 0.0000603 AC: 4 AN: 66358

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
Mutation Taster		=81/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1553686135; hg19: chr3-63898390;