Variant 2-68513563-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_173545.3(APLF):c.505A>G(p.Asn169Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,611,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

APLF
NM_173545.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.552

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062438548).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APLF	NM_173545.3 linkuse as main transcript	c.505A>G	p.Asn169Asp	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.505A>G	p.Asn169Asp	missense_variant	5/10	1	NM_173545.3	P1
APLF	ENST00000445692.5 linkuse as main transcript	c.505A>G	p.Asn169Asp	missense_variant, NMD_transcript_variant	5/11	5
APLF	ENST00000529851.5 linkuse as main transcript	c.433A>G	p.Asn145Asp	missense_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes

AF:

0.000606

AC:

AN:

151738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00347

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000723

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000672

AC:

168

AN:

250060

Hom.:

AF XY:

0.000592

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000589

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000584

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000563

AC:

821

AN:

1459272

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

402

AN XY:

725936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000877

Gnomad4 ASJ exome

AF:

0.00369

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000883

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.000913

GnomAD4 genome

AF:

0.000606

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.000606

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00347

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000723

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.000774

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000656

EpiControl

AF:

0.000949

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.505A>G (p.N169D) alteration is located in exon 5 (coding exon 5) of the APLF gene. This alteration results from a A to G substitution at nucleotide position 505, causing the asparagine (N) at amino acid position 169 to be replaced by an aspartic acid (D). 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

0.071

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

DANN

Benign

0.63

DEOGEN2

Benign

0.026

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.63

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.64

REVEL

Benign

0.0080

Sift

Benign

0.84

Sift4G

Benign

0.86

Polyphen

0.039

Vest4

0.10

MVP

0.25

MPC

0.044

ClinPred

0.0097

GERP RS

-5.3

Varity_R

0.045

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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