Variant chr2-68513603-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_173545.3(APLF):c.545G>A(p.Arg182Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000365 in 1,611,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

APLF
NM_173545.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.61

Variant links:

Genes affected

APLF (HGNC:28724): (aprataxin and PNKP like factor) Enables DNA-(apurinic or apyrimidinic site) endonuclease activity; nuclease activity; and nucleotide binding activity. Involved in double-strand break repair via nonhomologous end joining and single strand break repair. Acts upstream of or within positive regulation of DNA ligation. Located in nucleoplasm. Is active in site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

APLF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a mutagenesis_site Reduced interaction with XRCC5 and XRCC6; impaired localization to the nucleus. (size 0) in uniprot entity APLF_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023345232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APLF	NM_173545.3 linkuse as main transcript	c.545G>A	p.Arg182Lys	missense_variant	5/10	ENST00000303795.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
APLF	ENST00000303795.9 linkuse as main transcript	c.545G>A	p.Arg182Lys	missense_variant	5/10	1	NM_173545.3	P1
APLF	ENST00000445692.5 linkuse as main transcript	c.545G>A	p.Arg182Lys	missense_variant, NMD_transcript_variant	5/11	5
APLF	ENST00000529851.5 linkuse as main transcript	c.473G>A	p.Arg158Lys	missense_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes

AF:

0.000330

AC:

AN:

151696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000461

Gnomad ASJ

AF:

0.00347

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000384

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000379

AC:

AN:

250596

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000369

AC:

538

AN:

1459674

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

246

AN XY:

726126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00369

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000360

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000329

AC:

AN:

151814

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000461

Gnomad4 ASJ

AF:

0.00347

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000384

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000328

EpiControl

AF:

0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.545G>A (p.R182K) alteration is located in exon 5 (coding exon 5) of the APLF gene. This alteration results from a G to A substitution at nucleotide position 545, causing the arginine (R) at amino acid position 182 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

M_CAP

Benign

0.0062

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

2.9

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Benign

0.29

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.43

MVP

0.61

MPC

0.28

ClinPred

0.16

GERP RS

6.2

Varity_R

0.87

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over