Genetic Variant ATXN7:p.Gln39del (chr3-63912684-GGCA-G) – 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.116_118delAGC(p.Gln39del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00328 in 1,078,090 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0059 ( 8 hom., cov: 23)

Exomes 𝑓: 0.0029 ( 3 hom. )

Consequence

ATXN7
NM_001377405.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign no assertion criteria provided B:2

Conservation

PhyloP100: 4.60

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:

Genome browser will be placed here

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-GGCA-G is Benign according to our data. Variant chr3-63912684-GGCA-G is described in ClinVar as Benign. ClinVar VariationId is 1328067.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00589 (852/144714) while in subpopulation AFR AF = 0.0169 (676/39996). AF 95% confidence interval is 0.0158. There are 8 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 852 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.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	Exon 3 of 13	NP_001364334.1	O15265-1
ATXN7	NM_001177387.1		c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	Exon 2 of 13	NP_001170858.1	O15265-2
ATXN7	NM_000333.4		c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	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_118delAGC	p.Gln39del	disruptive_inframe_deletion	Exon 3 of 13	ENSP00000501377.1	O15265-1
ATXN7	ENST00000295900.10	TSL:1	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	Exon 3 of 13	ENSP00000295900.6	O15265-1
ATXN7	ENST00000522345.2	TSL:2	c.116_118delAGC	p.Gln39del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes

AF:

0.00591

AC:

855

AN:

144614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00415

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00230

Gnomad SAS

AF:

0.00340

Gnomad FIN

AF:

0.000118

Gnomad MID

AF:

0.00987

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.00697

GnomAD2 exomes

AF:

0.0230

AC:

238

AN:

10356

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0349

Gnomad ASJ exome

AF:

0.0436

Gnomad EAS exome

AF:

0.0588

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0256

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.00288

AC:

2689

AN:

933376

Hom.:

AF XY:

0.00318

AC XY:

1406

AN XY:

441998

show subpopulations

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

African (AFR)

AF:

0.0194

AC:

340

AN:

17568

American (AMR)

AF:

0.0168

AC:

AN:

5130

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

AN:

8270

East Asian (EAS)

AF:

0.00918

AC:

AN:

9372

South Asian (SAS)

AF:

0.00587

AC:

116

AN:

19754

European-Finnish (FIN)

AF:

0.00934

AC:

172

AN:

18414

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

2082

European-Non Finnish (NFE)

AF:

0.00208

AC:

1704

AN:

820046

Other (OTH)

AF:

0.00394

AC:

129

AN:

32740

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.378

Heterozygous variant carriers

174

348

522

696

870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00589

AC:

852

AN:

144714

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

410

AN XY:

70408

show subpopulations

African (AFR)

AF:

0.0169

AC:

676

AN:

39996

American (AMR)

AF:

0.00415

AC:

AN:

14702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.00231

AC:

AN:

4766

South Asian (SAS)

AF:

0.00340

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.000118

AC:

AN:

8510

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

65440

Other (OTH)

AF:

0.00690

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.6

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

3-63912684-GGCAGCAGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCA

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