chr2-68513563-A-G

Variant names:

• chr2-68513563-A-G
• rs145654399
• NM_173545.3:c.505A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173545.3(APLF):​c.505A>G​(p.Asn169Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,611,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: APLF NM_173545.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.552
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062438548).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.505A>G	p.Asn169Asp	missense	Exon 5 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.505A>G	p.Asn169Asp	missense	Exon 5 of 10	ENSP00000307004.4	Q8IW19
	APLF	ENST00000963710.1		c.505A>G	p.Asn169Asp	missense	Exon 5 of 9	ENSP00000633769.1
	APLF	ENST00000905978.1		c.433A>G	p.Asn145Asp	missense	Exon 4 of 9	ENSP00000576037.1

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 92 AN: 151738 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000723

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000672 AC: 168 AN: 250060 AF XY: 0.000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000563 AC: 821 AN: 1459272 Hom.: 2 Cov.: 31 AF XY: 0.000554 AC XY: 402 AN XY: 725936

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.000877 AC: 39 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00369 AC: 96 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000883 AC: 76 AN: 86116

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53388

Middle Eastern (MID) AF: 0.00679 AC: 39 AN: 5740

European-Non Finnish (NFE) AF: 0.000463 AC: 514 AN: 1110346

Other (OTH) AF: 0.000913 AC: 55 AN: 60226

GnomAD4 genome AF: 0.000606 AC: 92 AN: 151856 Hom.: 0 Cov.: 32 AF XY: 0.000606 AC XY: 45 AN XY: 74236

African (AFR) AF: 0.0000964 AC: 4 AN: 41512

American (AMR) AF: 0.00138 AC: 21 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000723 AC: 49 AN: 67790

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.000774

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000656

EpiControl AF: 0.000949

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	0.071
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.63
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.55
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.0080
Sift	Benign	0.84	T
Sift4G	Benign	0.86	T
Polyphen		0.039	B
Vest4		0.10
MVP		0.25
MPC		0.044
ClinPred		0.0097	T
GERP RS		-5.3
Varity_R		0.045
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145654399; hg19: chr2-68740695;