2-68502762-C-T

Variant names:

• chr2-68502762-C-T
• rs377751152
• NM_173545.3:c.200C>T

Variant summary

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

The NM_173545.3(APLF):​c.200C>T​(p.Ser67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000703 in 1,421,928 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: 0.0000070 (0 hom.)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• 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 2 ACMG points.

• 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.200C>T	p.Ser67Leu	missense	Exon 3 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.200C>T	p.Ser67Leu	missense	Exon 3 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.200C>T	p.Ser67Leu	missense	Exon 3 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.128C>T	p.Ser43Leu	missense	Exon 2 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000912 AC: 2 AN: 219416 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000954

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000703 AC: 10 AN: 1421928 Hom.: 0 Cov.: 30 AF XY: 0.00000708 AC XY: 5 AN XY: 706602

African (AFR) AF: 0.00 AC: 0 AN: 30974

American (AMR) AF: 0.0000286 AC: 1 AN: 34938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 37606

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00000546 AC: 6 AN: 1098774

Other (OTH) AF: 0.0000341 AC: 2 AN: 58566

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.080
Sift	Benign	0.071	T
Sift4G	Benign	0.14	T
Polyphen		0.67	P
Vest4		0.28
MVP		0.37
MPC		0.18
ClinPred		0.92	D
GERP RS		3.4
Varity_R		0.43
gMVP		0.32
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377751152; hg19: chr2-68729894;