Genetic Variant APLF:p.Arg99Ser (chr2-68502857-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173545.3(APLF):c.295C>A(p.Arg99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

APLF
NM_173545.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.501

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18809658).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173545.3. 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
	APLF	NM_173545.3	MANE Select	c.295C>A	p.Arg99Ser	missense	Exon 3 of 10	NP_775816.1	Q8IW19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APLF	ENST00000303795.9	TSL:1 MANE Select	c.295C>A	p.Arg99Ser	missense	Exon 3 of 10	ENSP00000307004.4	Q8IW19
APLF	ENST00000963710.1		c.295C>A	p.Arg99Ser	missense	Exon 3 of 9	ENSP00000633769.1
APLF	ENST00000905978.1		c.223C>A	p.Arg75Ser	missense	Exon 2 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32826

American (AMR)

AF:

0.00

AC:

AN:

42932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39018

South Asian (SAS)

AF:

0.00

AC:

AN:

84872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109384

Other (OTH)

AF:

0.0000167

AC:

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

3.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.63

M_CAP

Benign

0.0066

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

PhyloP100

-0.50

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.13

Sift

Benign

0.077

Sift4G

Uncertain

0.027

Polyphen

0.83

Vest4

0.22

MutPred

0.46

Gain of methylation at K95 (P = 0.0477)

MVP

0.17

MPC

0.043

ClinPred

0.65

GERP RS

1.4

Varity_R

0.61

gMVP

0.56

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over