2-68467756-C-T

Variant names:

• chr2-68467756-C-T
• NM_173545.3:c.25C>T

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.25C>T​(p.Pro9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,508 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: not found (cov: 32)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• 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=0.26350254).

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.25C>T	p.Pro9Ser	missense	Exon 1 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.25C>T	p.Pro9Ser	missense	Exon 1 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.25C>T	p.Pro9Ser	missense	Exon 1 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.25C>T	p.Pro9Ser	missense	Exon 1 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082508 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 511360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23022

American (AMR) AF: 0.00 AC: 0 AN: 8412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14370

East Asian (EAS) AF: 0.00 AC: 0 AN: 26532

South Asian (SAS) AF: 0.00 AC: 0 AN: 19600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4394

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 920030

Other (OTH) AF: 0.00 AC: 0 AN: 43822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Uncertain	0.44
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.18
MutPred		0.20		Gain of phosphorylation at P9 (P = 0.0348)
MVP		0.52
MPC		0.093
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.53
Mutation Taster		=41/59	disease causing

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

hg19: chr2-68694888; COSMIC: COSV105155523; COSMIC: COSV105155523;