rs148022399

Variant names:

• chr2-68513603-G-A
• rs148022399
• NM_173545.3:c.545G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-68513603-G-A
• chr2-68513603-G-C
• chr2-68513603-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• Publications: 4 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.023345232).

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.545G>A	p.Arg182Lys	missense	Exon 5 of 10	NP_775816.1	Q8IW19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLF	ENST00000303795.9	TSL:1 MANE Select	c.545G>A	p.Arg182Lys	missense	Exon 5 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.545G>A	p.Arg182Lys	missense	Exon 5 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.473G>A	p.Arg158Lys	missense	Exon 4 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 50 AN: 151696 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000379 AC: 95 AN: 250596 AF XY: 0.000288

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 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.: 0 Cov.: 31 AF XY: 0.000339 AC XY: 246 AN XY: 726126

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.000135 AC: 6 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00369 AC: 96 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86146

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.000360 AC: 400 AN: 1110526

Other (OTH) AF: 0.000531 AC: 32 AN: 60258

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151814 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74208

African (AFR) AF: 0.0000964 AC: 4 AN: 41498

American (AMR) AF: 0.000461 AC: 7 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000384 AC: 26 AN: 67772

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000466 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000328

EpiControl AF: 0.000712

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.61
MPC		0.28
ClinPred		0.16	T
GERP RS		6.2
Varity_R		0.87
gMVP		0.47
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs148022399; hg19: chr2-68740735;