3-63912684-G-GGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3BA1

The NM_001377405.1(ATXN7):c.116_118dupAGC(p.Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0327 in 1,083,874 control chromosomes in the GnomAD database, including 941 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.063 ( 544 hom., cov: 23)

Exomes 𝑓: 0.028 ( 397 hom. )

Consequence

ATXN7
NM_001377405.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.10

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P
spinocerebellar ataxia type 7
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ATXN7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001377405.1

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN7	NM_001377405.1	MANE Select	c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
ATXN7	NM_001177387.1		c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
ATXN7	NM_000333.4		c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	NP_000324.1	O15265-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN7	ENST00000674280.1	MANE Select	c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
ATXN7	ENST00000295900.10	TSL:1	c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
ATXN7	ENST00000522345.2	TSL:2	c.116_118dupAGC	p.Gln39dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes

AF:

0.0625

AC:

9030

AN:

144576

Hom.:

542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.00442

Gnomad AMR

AF:

0.0355

Gnomad ASJ

AF:

0.0353

Gnomad EAS

AF:

0.0416

Gnomad SAS

AF:

0.0289

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.0230

Gnomad NFE

AF:

0.0235

Gnomad OTH

AF:

0.0428

GnomAD2 exomes

AF:

0.0267

AC:

277

AN:

10356

AF XY:

0.0281

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.0628

Gnomad ASJ exome

AF:

0.0640

Gnomad EAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.00875

Gnomad NFE exome

AF:

0.0308

Gnomad OTH exome

AF:

0.0400

GnomAD4 exome

AF:

0.0281

AC:

26375

AN:

939196

Hom.:

397

Cov.:

AF XY:

0.0276

AC XY:

12298

AN XY:

445070

show subpopulations

African (AFR)

AF:

0.162

AC:

2861

AN:

17698

American (AMR)

AF:

0.0379

AC:

198

AN:

5226

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

264

AN:

8372

East Asian (EAS)

AF:

0.0381

AC:

365

AN:

9576

South Asian (SAS)

AF:

0.0288

AC:

574

AN:

19934

European-Finnish (FIN)

AF:

0.0148

AC:

279

AN:

18830

Middle Eastern (MID)

AF:

0.0361

AC:

AN:

2076

European-Non Finnish (NFE)

AF:

0.0249

AC:

20571

AN:

824498

Other (OTH)

AF:

0.0360

AC:

1188

AN:

32986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1315

2630

3945

5260

6575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1090

2180

3270

4360

5450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0626

AC:

9057

AN:

144678

Hom.:

544

Cov.:

AF XY:

0.0614

AC XY:

4323

AN XY:

70392

show subpopulations

African (AFR)

AF:

0.157

AC:

6276

AN:

39968

American (AMR)

AF:

0.0356

AC:

524

AN:

14702

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

119

AN:

3374

East Asian (EAS)

AF:

0.0420

AC:

200

AN:

4764

South Asian (SAS)

AF:

0.0289

AC:

136

AN:

4708

European-Finnish (FIN)

AF:

0.0197

AC:

168

AN:

8508

Middle Eastern (MID)

AF:

0.0248

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0235

AC:

1535

AN:

65436

Other (OTH)

AF:

0.0433

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

380

760

1141

1521

1901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00250

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Mutation Taster

=68/32

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over