2-68490253-A-G

Variant names:

• chr2-68490253-A-G
• rs770512397
• NM_173545.3:c.160A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173545.3(APLF):​c.160A>G​(p.Ile54Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41379502).

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.160A>G	p.Ile54Val	missense	Exon 2 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.160A>G	p.Ile54Val	missense	Exon 2 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.160A>G	p.Ile54Val	missense	Exon 2 of 9	ENSP00000633769.1
	APLF	ENST00000963711.1		c.160A>G	p.Ile54Val	missense	Exon 2 of 9	ENSP00000633770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249822 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.19		Gain of methylation at K55 (P = 0.0543)
MVP		0.21
MPC		0.26
ClinPred		0.70	D
GERP RS		5.9
Varity_R		0.27
gMVP		0.25
Mutation Taster		=80/20	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: rs770512397; hg19: chr2-68717385;