9-32986032-T-TAAAAAAAAACAA

Variant names:

• chr9-32986032-T-TAAAAAAAAACAA
• rs1554664711
• NM_001195248.2:c.484-3_484-2insTTGTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001195248.2(APTX):​c.484-3_484-2insTTGTTTTTTTTT variant causes a splice region, intron 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (17 hom.)
  • Failed GnomAD Quality Control
• Consequence: APTX NM_001195248.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.384
• Publications: 0 publications found

Genes affected

APTX (HGNC:15984): (aprataxin) This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.[provided by RefSeq, Aug 2010]

APTX Gene-Disease associations (from GenCC):

• ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 9-32986032-T-TAAAAAAAAACAA is Benign according to our data. Variant chr9-32986032-T-TAAAAAAAAACAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446857.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2	c.484-3_484-2insTTGTTTTTTTTT		splice_region_variant, intron_variant	Intron 4 of 7	ENST00000379817.7	NP_001182177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7	c.484-3_484-2insTTGTTTTTTTTT		splice_region_variant, intron_variant	Intron 4 of 7	1	NM_001195248.2	ENSP00000369145.2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 18 AN: 14344 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000840

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00429

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00281 AC: 2015 AN: 717624 Hom.: 17 Cov.: 10 AF XY: 0.00302 AC XY: 1122 AN XY: 370912

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

African (AFR) AF: 0.00532 AC: 82 AN: 15418

American (AMR) AF: 0.00590 AC: 146 AN: 24728

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 40 AN: 16082

East Asian (EAS) AF: 0.0149 AC: 361 AN: 24302

South Asian (SAS) AF: 0.00725 AC: 372 AN: 51308

European-Finnish (FIN) AF: 0.000880 AC: 25 AN: 28422

Middle Eastern (MID) AF: 0.00131 AC: 3 AN: 2296

European-Non Finnish (NFE) AF: 0.00175 AC: 914 AN: 523312

Other (OTH) AF: 0.00227 AC: 72 AN: 31756

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00126 AC: 18 AN: 14340 Hom.: 0 Cov.: 0 AF XY: 0.00181 AC XY: 12 AN XY: 6640

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

African (AFR) AF: 0.000774 AC: 4 AN: 5166

American (AMR) AF: 0.000846 AC: 1 AN: 1182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 318

East Asian (EAS) AF: 0.00433 AC: 2 AN: 462

South Asian (SAS) AF: 0.00 AC: 0 AN: 384

European-Finnish (FIN) AF: 0.00180 AC: 1 AN: 556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00165 AC: 10 AN: 6050

Other (OTH) AF: 0.00 AC: 0 AN: 120

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1554664711; hg19: chr9-32986030;