Genetic Variant ATXN7:p.Gln37_Gln39dup (chr3-63912684-G-GGCAGCAGCA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001377405.1(ATXN7):c.110_118dupAGCAGCAGC(p.Gln37_Gln39dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.046 in 1,086,962 control chromosomes in the GnomAD database, including 796 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.034 ( 92 hom., cov: 23)

Exomes 𝑓: 0.048 ( 704 hom. )

Consequence

ATXN7
NM_001377405.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B: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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001377405.1

BP6

Variant 3-63912684-G-GGCAGCAGCA is Benign according to our data. Variant chr3-63912684-G-GGCAGCAGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3033271.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0342 (4953/144692) while in subpopulation NFE AF = 0.0483 (3159/65426). AF 95% confidence interval is 0.0469. There are 92 homozygotes in GnomAd4. There are 2376 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 4953 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN7	NM_001377405.1	MANE Select	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
ATXN7	NM_001177387.1		c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
ATXN7	NM_000333.4		c.110_118dupAGCAGCAGC	p.Gln37_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.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
ATXN7	ENST00000295900.10	TSL:1	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
ATXN7	ENST00000522345.2	TSL:2	c.110_118dupAGCAGCAGC	p.Gln37_Gln39dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes

AF:

0.0342

AC:

4952

AN:

144590

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.0618

Gnomad AMR

AF:

0.0341

Gnomad ASJ

AF:

0.0528

Gnomad EAS

AF:

0.00649

Gnomad SAS

AF:

0.0227

Gnomad FIN

AF:

0.0356

Gnomad MID

AF:

0.0296

Gnomad NFE

AF:

0.0483

Gnomad OTH

AF:

0.0369

GnomAD2 exomes

AF:

0.0215

AC:

223

AN:

10356

AF XY:

0.0226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00698

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.0478

AC:

45017

AN:

942270

Hom.:

704

Cov.:

AF XY:

0.0474

AC XY:

21160

AN XY:

446526

show subpopulations

African (AFR)

AF:

0.0103

AC:

182

AN:

17716

American (AMR)

AF:

0.0349

AC:

184

AN:

5278

Ashkenazi Jewish (ASJ)

AF:

0.0596

AC:

501

AN:

8400

East Asian (EAS)

AF:

0.00655

AC:

AN:

9614

South Asian (SAS)

AF:

0.0310

AC:

621

AN:

20016

European-Finnish (FIN)

AF:

0.0277

AC:

522

AN:

18850

Middle Eastern (MID)

AF:

0.0243

AC:

AN:

2096

European-Non Finnish (NFE)

AF:

0.0502

AC:

41537

AN:

827206

Other (OTH)

AF:

0.0410

AC:

1356

AN:

33094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

2137

4274

6411

8548

10685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1978

3956

5934

7912

9890

<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:

0.0342

AC:

4953

AN:

144692

Hom.:

Cov.:

AF XY:

0.0338

AC XY:

2376

AN XY:

70390

show subpopulations

African (AFR)

AF:

0.0133

AC:

533

AN:

39994

American (AMR)

AF:

0.0340

AC:

500

AN:

14702

Ashkenazi Jewish (ASJ)

AF:

0.0528

AC:

178

AN:

3372

East Asian (EAS)

AF:

0.00650

AC:

AN:

4766

South Asian (SAS)

AF:

0.0236

AC:

111

AN:

4706

European-Finnish (FIN)

AF:

0.0356

AC:

303

AN:

8508

Middle Eastern (MID)

AF:

0.0284

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0483

AC:

3159

AN:

65426

Other (OTH)

AF:

0.0365

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

221

442

664

885

1106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0150

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ATXN7-related disorder (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Mutation Taster

=68/32

polymorphism

(source)

Splicing

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

Publications

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3-63912684-GGCAGCAGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

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