rs1048945

Positions:

• chr14-20456008-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001641.4(APEX1):​c.153G>C​(p.Gln51His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,614,190 control chromosomes in the GnomAD database, including 1,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (55 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1007 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

Genes affected

APEX1 (HGNC:587): (apurinic/apyrimidinic endodeoxyribonuclease 1) The APEX gene encodes the major AP endonuclease in human cells. It encodes the APEX endonuclease, a DNA repair enzyme with apurinic/apyrimidinic (AP) activity. Such AP activity sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. The AP sites are the most frequent pre-mutagenic lesions that can prevent normal DNA replication. Splice variants have been found for this gene; all encode the same protein. Disruptions in the biological functions related to APEX are associated with many various malignancies and neurodegenerative diseases.[provided by RefSeq, Dec 2019]

APEX1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004014522).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0237 (3605/152314) while in subpopulation NFE AF= 0.0399 (2716/68034). AF 95% confidence interval is 0.0387. There are 55 homozygotes in gnomad4. There are 1637 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APEX1	NM_001641.4	c.153G>C	p.Gln51His	missense_variant	3/5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.153G>C	p.Gln51His	missense_variant	3/5		NP_001231178.1
APEX1	NM_080648.3	c.153G>C	p.Gln51His	missense_variant	3/5		NP_542379.1
APEX1	NM_080649.3	c.153G>C	p.Gln51His	missense_variant	3/5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.153G>C	p.Gln51His	missense_variant	3/5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3604 AN: 152196 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0209 AC: 5263 AN: 251436 Hom.: 83 AF XY: 0.0210 AC XY: 2849 AN XY: 135898

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0366

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0344 AC: 50306 AN: 1461876 Hom.: 1007 Cov.: 32 AF XY: 0.0333 AC XY: 24243 AN XY: 727236

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0237 AC: 3605 AN: 152314 Hom.: 55 Cov.: 32 AF XY: 0.0220 AC XY: 1637 AN XY: 74464

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0347 Hom.: 84

Bravo AF: 0.0241

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0384 AC: 148

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0376 AC: 323

ExAC AF: 0.0205 AC: 2493

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0380

EpiControl AF: 0.0387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T;T;T;T;.;T;T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	.;.;D;D;D;D;D;T;D;D;D
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;L;.;.;L;.;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.55	N;N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.054
Sift	Uncertain	0.026	D;D;D;T;D;T;D;T;T;T;T
Sift4G	Benign	0.074	T;T;D;D;T;D;T;D;T;T;T
Polyphen		0.14	B;B;.;.;B;.;.;.;.;.;.
Vest4		0.038
MutPred		0.20		Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);.;Gain of catalytic residue at P48 (P = 0.0016);.;.;
MPC		0.17
ClinPred		0.013	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.55

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: rs1048945; hg19: chr14-20924167; COSMIC: COSV105067964; COSMIC: COSV105067964;