Genetic Variant APTX:c.484-3_484-2insTGTTTTTTTTT (chr9-32986032-T-TAAAAAAAAACA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001195248.2(APTX):c.484-3_484-2insTGTTTTTTTTT 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

APTX
NM_001195248.2 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.384

Publications

0 publications found

Variant links:

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

APTX links:

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ACMG classification

Classification was made for transcript

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

BP6

Variant 9-32986032-T-TAAAAAAAAACA is Benign according to our data. Variant chr9-32986032-T-TAAAAAAAAACA is described in ClinVar as Likely_benign. ClinVar VariationId is 2693722.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000586 (421/718738) while in subpopulation EAS AF = 0.00196 (48/24444). AF 95% confidence interval is 0.00152. There are 3 homozygotes in GnomAdExome4. There are 224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2 link	c.484-3_484-2insTGTTTTTTTTT		splice_region_variant, intron_variant	Intron 4 of 7	ENST00000379817.7	NP_001182177.2	Q7Z2E3-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7 link	c.484-3_484-2insTGTTTTTTTTT		splice_region_variant, intron_variant	Intron 4 of 7	1	NM_001195248.2	ENSP00000369145.2		Q7Z2E3-7

Frequencies

GnomAD3 genomes

AF:

0.000278

AC:

AN:

14364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00258

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000329

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000586

AC:

421

AN:

718738

Hom.:

Cov.:

AF XY:

0.000603

AC XY:

224

AN XY:

371534

show subpopulations

African (AFR)

AF:

0.00110

AC:

AN:

15456

American (AMR)

AF:

0.00109

AC:

AN:

24798

Ashkenazi Jewish (ASJ)

AF:

0.000434

AC:

AN:

16114

East Asian (EAS)

AF:

0.00196

AC:

AN:

24444

South Asian (SAS)

AF:

0.00161

AC:

AN:

51516

European-Finnish (FIN)

AF:

0.000457

AC:

AN:

28438

Middle Eastern (MID)

AF:

0.000434

AC:

AN:

2306

European-Non Finnish (NFE)

AF:

0.000391

AC:

205

AN:

523876

Other (OTH)

AF:

0.000629

AC:

AN:

31790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000279

AC:

AN:

14360

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

AN XY:

6650

show subpopulations

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

African (AFR)

AF:

0.000193

AC:

AN:

5168

American (AMR)

AF:

0.00

AC:

AN:

1182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

320

East Asian (EAS)

AF:

0.00

AC:

AN:

464

South Asian (SAS)

AF:

0.00260

AC:

AN:

384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000330

AC:

AN:

6066

Other (OTH)

AF:

0.00

AC:

AN:

120

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000130562), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over