rs758426629

Variant names:

• chr2-68526127-A-G
• rs758426629
• NM_173545.3:c.689A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173545.3(APLF):​c.689A>G​(p.Gln230Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07544887).

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.689A>G	p.Gln230Arg	missense	Exon 6 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.689A>G	p.Gln230Arg	missense	Exon 6 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.689A>G	p.Gln230Arg	missense	Exon 6 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.617A>G	p.Gln206Arg	missense	Exon 5 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251140 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.20
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.049
Sift	Benign	0.18	T
Sift4G	Benign	0.48	T
Polyphen		0.099	B
Vest4		0.19
MutPred		0.17		Gain of MoRF binding (P = 0.0197)
MVP		0.27
MPC		0.057
ClinPred		0.22	T
GERP RS		3.0
Varity_R		0.056
gMVP		0.20
Mutation Taster		=94/6	polymorphism

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: rs758426629; hg19: chr2-68753259;