3-63912714-A-AGCAGCC

Variant names:

• chr3-63912714-A-AGCAGCC
• rs770364745
• NM_001377405.1:c.118_119insAGCCGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001377405.1(ATXN7):​c.118_119insAGCCGC​(p.Gln39_Pro40insGlnPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,212,244 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: ATXN7 NM_001377405.1 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001377405.1
• BP6: Variant 3-63912714-A-AGCAGCC is Benign according to our data. Variant chr3-63912714-A-AGCAGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 2653940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 443 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.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
	ATXN7	NM_001177387.1		c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
	ATXN7	NM_000333.4		c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	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_119insAGCCGC	p.Gln39_Pro40insGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
	ATXN7	ENST00000295900.10	TSL:1	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
	ATXN7	ENST00000522345.2	TSL:2	c.118_119insAGCCGC	p.Gln39_Pro40insGlnPro	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 442 AN: 146890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00413

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.000547

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00247

GnomAD2 exomes AF: 0.000125 AC: 4 AN: 32074 AF XY: 0.0000552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00195 AC: 2075 AN: 1065246 Hom.: 2 Cov.: 32 AF XY: 0.00193 AC XY: 984 AN XY: 510420

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

African (AFR) AF: 0.00497 AC: 104 AN: 20910

American (AMR) AF: 0.00114 AC: 13 AN: 11444

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 24 AN: 13266

East Asian (EAS) AF: 0.0000506 AC: 1 AN: 19744

South Asian (SAS) AF: 0.000270 AC: 7 AN: 25968

European-Finnish (FIN) AF: 0.000158 AC: 5 AN: 31596

Middle Eastern (MID) AF: 0.00258 AC: 7 AN: 2712

European-Non Finnish (NFE) AF: 0.00204 AC: 1837 AN: 899330

Other (OTH) AF: 0.00191 AC: 77 AN: 40276

⚠️ 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: 0.00301 AC: 443 AN: 146998 Hom.: 1 Cov.: 31 AF XY: 0.00295 AC XY: 211 AN XY: 71544

African (AFR) AF: 0.00576 AC: 233 AN: 40424

American (AMR) AF: 0.00148 AC: 22 AN: 14884

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 14 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.000630 AC: 3 AN: 4762

European-Finnish (FIN) AF: 0.000547 AC: 5 AN: 9136

Middle Eastern (MID) AF: 0.0280 AC: 8 AN: 286

European-Non Finnish (NFE) AF: 0.00231 AC: 153 AN: 66352

Other (OTH) AF: 0.00244 AC: 5 AN: 2048

Alfa AF: 0.000374 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;