3-63912714-A-AGCAGCAGCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001377405.1(ATXN7):c.118_119insAGCAGCCGC(p.Gln39_Pro40insGlnGlnPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 146,964 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0065 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0030 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

ATXN7
NM_001377405.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.825

Publications

3 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: G2P, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001377405.1

BS2

High AC in GnomAd4 at 948 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.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	NP_001364334.1	O15265-1
ATXN7	NM_001177387.1		c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 2 of 13	NP_001170858.1	O15265-2
ATXN7	NM_000333.4		c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	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.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000501377.1	O15265-1
ATXN7	ENST00000295900.10	TSL:1	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 3 of 13	ENSP00000295900.6	O15265-1
ATXN7	ENST00000522345.2	TSL:2	c.118_119insAGCAGCCGC	p.Gln39_Pro40insGlnGlnPro	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000428067.2	O15265-2

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

943

AN:

146860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00781

Gnomad ASJ

AF:

0.00767

Gnomad EAS

AF:

0.000830

Gnomad SAS

AF:

0.00651

Gnomad FIN

AF:

0.00241

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00938

GnomAD2 exomes

AF:

0.000655

AC:

AN:

32074

AF XY:

0.000607

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000568

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00132

Gnomad NFE exome

AF:

0.000516

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00303

AC:

3229

AN:

1064670

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

1521

AN XY:

510154

show subpopulations

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

African (AFR)

AF:

0.0109

AC:

228

AN:

20860

American (AMR)

AF:

0.00192

AC:

AN:

11434

Ashkenazi Jewish (ASJ)

AF:

0.00362

AC:

AN:

13252

East Asian (EAS)

AF:

0.00157

AC:

AN:

19738

South Asian (SAS)

AF:

0.00702

AC:

182

AN:

25914

European-Finnish (FIN)

AF:

0.00108

AC:

AN:

31584

Middle Eastern (MID)

AF:

0.00221

AC:

AN:

2714

European-Non Finnish (NFE)

AF:

0.00282

AC:

2534

AN:

898936

Other (OTH)

AF:

0.00358

AC:

144

AN:

40238

⚠️ 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: 0.299

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00645

AC:

948

AN:

146964

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

450

AN XY:

71528

show subpopulations

African (AFR)

AF:

0.0131

AC:

530

AN:

40404

American (AMR)

AF:

0.00780

AC:

116

AN:

14880

Ashkenazi Jewish (ASJ)

AF:

0.00767

AC:

AN:

3388

East Asian (EAS)

AF:

0.000832

AC:

AN:

4808

South Asian (SAS)

AF:

0.00652

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00241

AC:

AN:

9134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00298

AC:

198

AN:

66352

Other (OTH)

AF:

0.0103

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000312

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.82

Mutation Taster

=81/19

polymorphism

(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