3-63912714-A-AGCAGCAGCAGCAGCAGCAGCAGCAGCC

Variant names:

• chr3-63912714-A-AGCAGCAGCAGCAGCAGCAGCAGCAGCC
• rs770364745
• NM_001377405.1:c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001377405.1(ATXN7):​c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC​(p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,212,566 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 31)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.825
• Publications: 3 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1

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.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	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.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.118_119insAGCAGCAGCAGCAGCAGCAGCAGCCGC	p.Gln39_Pro40insGlnGlnGlnGlnGlnGlnGlnGlnPro	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.0000613 AC: 9 AN: 146902 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 9.38e-7 AC: 1 AN: 1065664 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 510618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20932

American (AMR) AF: 0.00 AC: 0 AN: 11452

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 19748

South Asian (SAS) AF: 0.00 AC: 0 AN: 25970

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 899676

Other (OTH) AF: 0.0000248 AC: 1 AN: 40290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000613 AC: 9 AN: 146902 Hom.: 0 Cov.: 31 AF XY: 0.0000700 AC XY: 5 AN XY: 71430

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000198 AC: 8 AN: 40312

American (AMR) AF: 0.00 AC: 0 AN: 14866

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4822

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66366

Other (OTH) AF: 0.000494 AC: 1 AN: 2026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00291033), which strongly suggests a high chance of mosaicism in these individuals.

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: rs770364745; hg19: chr3-63898390;