2-68513603-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_173545.3(APLF):​c.545G>T​(p.Arg182Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R182K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 4 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

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>T	p.Arg182Met	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>T	p.Arg182Met	missense	Exon 5 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.545G>T	p.Arg182Met	missense	Exon 5 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.473G>T	p.Arg158Met	missense	Exon 4 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.34		Loss of methylation at K183 (P = 0.031)
MVP		0.59
MPC		0.29
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.85
gMVP		0.59
Mutation Taster		=50/50

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: rs148022399; hg19: chr2-68740735;