9-32984659-A-T

Variant names:

• chr9-32984659-A-T
• rs141195622
• NM_001195248.2:c.742T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/22 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:6 B:4
• Conservation: PhyloP100: -1.02
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• 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 VariationId is 214122.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195248.2. 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
	APTX	NM_001195248.2	MANE Select	c.742T>A	p.Leu248Met	missense	Exon 6 of 8	NP_001182177.2
	APTX	NM_001195249.2		c.742T>A	p.Leu248Met	missense	Exon 6 of 8	NP_001182178.1
	APTX	NM_001368995.1		c.742T>A	p.Leu248Met	missense	Exon 6 of 8	NP_001355924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.742T>A	p.Leu248Met	missense	Exon 6 of 8	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.742T>A	p.Leu248Met	missense	Exon 7 of 9	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.742T>A	p.Leu248Met	missense	Exon 6 of 8	ENSP00000419846.1

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

GnomAD2 exomes AF: 0.00135 AC: 339 AN: 251318 AF XY: 0.00138

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00165 AC: 74 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00210 AC: 2340 AN: 1112008

Other (OTH) AF: 0.00157 AC: 95 AN: 60396

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

African (AFR) AF: 0.000626 AC: 26 AN: 41556

American (AMR) AF: 0.00405 AC: 62 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (4)
-	2	2	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	8.6
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	0.85	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.40
Sift	Benign	0.049	D
Sift4G	Benign	0.18	T
Polyphen		0.86	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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs141195622; hg19: chr9-32984657; COSMIC: COSV108103909; COSMIC: COSV108103909;