chr14-92071010-C-CTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr14-92071010-C-CTGCTGCTGCTGCTGCTGCTG
• rs1555397062
• NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCA​(p.Gly306GlnfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.073 (575 hom., cov: 20)
  • Exomes 𝑓: 0.095 (6292 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.168
• Publications: 0 publications found

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ATXN3 Gene-Disease associations (from GenCC):

• Machado-Joseph disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Machado-Joseph disease type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-92071010-C-CTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CTGCTGCTGCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 1209890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. 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
	ATXN3	NM_004993.6	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCA	p.Gly306GlnfsTer32	frameshift	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.870_871insCAGCAGCAGCAGCAGCAGCA	p.Gly291GlnfsTer32	frameshift	Exon 9 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.762_763insCAGCAGCAGCAGCAGCAGCA	p.Gly255GlnfsTer32	frameshift	Exon 8 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCA	p.Gly306GlnfsTer32	frameshift	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.915_916insCAGCAGCAGCAGCAGCAGCA	p.Gly306GlnfsTer32	frameshift	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.870_871insCAGCAGCAGCAGCAGCAGCA	p.Gly291GlnfsTer32	frameshift	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.0731 AC: 10413 AN: 142368 Hom.: 576 Cov.: 20

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0228

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00259

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0691

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0947 AC: 124068 AN: 1310102 Hom.: 6292 Cov.: 92 AF XY: 0.0936 AC XY: 61338 AN XY: 655086

African (AFR) AF: 0.0182 AC: 501 AN: 27518

American (AMR) AF: 0.0420 AC: 1698 AN: 40434

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2724 AN: 24326

East Asian (EAS) AF: 0.00115 AC: 43 AN: 37446

South Asian (SAS) AF: 0.0461 AC: 3656 AN: 79392

European-Finnish (FIN) AF: 0.136 AC: 6650 AN: 48790

Middle Eastern (MID) AF: 0.105 AC: 538 AN: 5140

European-Non Finnish (NFE) AF: 0.104 AC: 103624 AN: 992072

Other (OTH) AF: 0.0843 AC: 4634 AN: 54984

GnomAD4 genome AF: 0.0731 AC: 10413 AN: 142478 Hom.: 575 Cov.: 20 AF XY: 0.0748 AC XY: 5178 AN XY: 69224

African (AFR) AF: 0.0190 AC: 690 AN: 36308

American (AMR) AF: 0.0489 AC: 705 AN: 14410

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 351 AN: 3412

East Asian (EAS) AF: 0.00259 AC: 12 AN: 4634

South Asian (SAS) AF: 0.0459 AC: 198 AN: 4310

European-Finnish (FIN) AF: 0.165 AC: 1635 AN: 9882

Middle Eastern (MID) AF: 0.110 AC: 31 AN: 282

European-Non Finnish (NFE) AF: 0.100 AC: 6637 AN: 66400

Other (OTH) AF: 0.0683 AC: 134 AN: 1962

Alfa AF: 0.225 Hom.: 51

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=99/101	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1555397062; hg19: chr14-92537354; COSMIC: COSV106061532; COSMIC: COSV106061532;