9-32984659-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_001195248.2(APTX):c.742T>A(p.Leu248Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,180 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L248L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: -1.02

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a domain HIT (size 105) in uniprot entity APTX_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in NM_001195248.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.01604551).
• BP6: Variant 9-32984659-A-T is Benign according to our data. Variant chr9-32984659-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214122.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00178 (271/152290) while in subpopulation AMR AF= 0.00405 (62/15294). AF 95% confidence interval is 0.00325. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2	c.742T>A	p.Leu248Met	missense_variant	6/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7	c.742T>A	p.Leu248Met	missense_variant	6/8	1	NM_001195248.2	P1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00135 AC: 339 AN: 251318 Hom.: 0 AF XY: 0.00138 AC XY: 188 AN XY: 135826

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00177 AC: 2593 AN: 1461890 Hom.: 5 Cov.: 32 AF XY: 0.00177 AC XY: 1285 AN XY: 727246

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74464

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00172

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00138 AC: 168

EpiCase AF: 0.00262

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	Observed in in individuals with ataxia in published literature; however, a second APTX variant was not detected and L248M was identified in unaffected family members (Castellotti et al., 2011); Published functional studies indicate that although this variant has a stabilizing effect it impairs active site assembly (Tumbale et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637650, 21465257, 29934293, 26285866) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	APTX: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2015	- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 16, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 20, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported but pathogenicity of these changes is unclear [PMID 26285866] -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	The APTX c.742T>A; p.Leu248Met variant (rs141195622), is reported in the literature in at least one individual affected with ataxia with oculomotor apraxia type 1 (van Minkelen 2015). This variant is reported in ClinVar (Variation ID: 214122), and is found in the general population with an overall allele frequency of 0.13% (373/277,044 alleles) in the Genome Aggregation Database. The leucine at codon 248 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Leu248Met variant is uncertain at this time. Pathogenic variants in the APTX gene are inherited in an autosomal recessive manner and are associated with early-onset ataxia with oculomotor apraxia and hypoalbuminemia (MIM: 208920). References: van Minkelen R et al. Complete APTX deletion in a patient with ataxia with oculomotor apraxia type 1. BMC Med Genet. 2015 Aug 19;16:61. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	8.6
Dann	Uncertain	0.98
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.78	T;T;T;T;.;T;.;.;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	0.85	L;.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.85	N;.;.;N;N;N;N;N;N;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.049	D;.;.;T;T;T;T;T;T;.;D;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.86, 0.24, 0.89, 0.89	.;.;P;B;.;P;.;.;.;.;.;P
Vest4		0.34
MVP		0.62
MPC		0.10
ClinPred		0.029	T
GERP RS		-7.1
Varity_R		0.23
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs141195622; hg19: chr9-32984657;