2-68513204-C-G

Variant names:

• chr2-68513204-C-G
• rs370287962
• NM_173545.3:c.466C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173545.3(APLF):​c.466C>G​(p.Gln156Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.153

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06610057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLF	NM_173545.3	c.466C>G	p.Gln156Glu	missense_variant	Exon 4 of 10	ENST00000303795.9	NP_775816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLF	ENST00000303795.9	c.466C>G	p.Gln156Glu	missense_variant	Exon 4 of 10	1	NM_173545.3	ENSP00000307004.4
APLF	ENST00000445692.5	n.466C>G		non_coding_transcript_exon_variant	Exon 4 of 11	5		ENSP00000393403.1
APLF	ENST00000529851.5	n.394C>G		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000432297.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.466C>G (p.Q156E) alteration is located in exon 4 (coding exon 4) of the APLF gene. This alteration results from a C to G substitution at nucleotide position 466, causing the glutamine (Q) at amino acid position 156 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.67
DANN	Benign	0.16
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.018
Sift	Benign	0.75	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.13		Loss of methylation at K154 (P = 0.0794);
MVP		0.24
MPC		0.052
ClinPred		0.88	D
GERP RS		1.3
Varity_R		0.046
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs370287962; hg19: chr2-68740336;