rs3136814

Variant names:

• chr14-20455138-A-C
• rs3136814
• NM_001641.4:c.-325A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001641.4(APEX1):​c.-325A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 348,230 control chromosomes in the GnomAD database, including 803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (480 hom., cov: 33)
  • Exomes 𝑓: 0.045 (323 hom.)
• Consequence: APEX1 NM_001641.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 11 publications found

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]

OSGEP (HGNC:18028): (O-sialoglycoprotein endopeptidase) Predicted to enable N(6)-L-threonylcarbamoyladenine synthase activity and metal ion binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytoplasm; nuclear speck; and plasma membrane. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 3. [provided by Alliance of Genome Resources, Apr 2022]

OSGEP Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 3

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-20455138-A-C is Benign according to our data. Variant chr14-20455138-A-C is described in ClinVar as Benign. ClinVar VariationId is 1275114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.-325A>C		upstream_gene_variant		ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.-320A>C		upstream_gene_variant			NP_001231178.1
APEX1	NM_080648.3	c.-259A>C		upstream_gene_variant			NP_542379.1
APEX1	NM_080649.3	c.-269A>C		upstream_gene_variant			NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.-325A>C		upstream_gene_variant		1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9889 AN: 152124 Hom.: 478 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0515

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0621

GnomAD4 exome AF: 0.0446 AC: 8741 AN: 195986 Hom.: 323 Cov.: 0 AF XY: 0.0488 AC XY: 5050 AN XY: 103450

African (AFR) AF: 0.116 AC: 712 AN: 6142

American (AMR) AF: 0.0493 AC: 309 AN: 6272

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 184 AN: 5520

East Asian (EAS) AF: 0.0216 AC: 233 AN: 10786

South Asian (SAS) AF: 0.0997 AC: 2412 AN: 24190

European-Finnish (FIN) AF: 0.0240 AC: 293 AN: 12200

Middle Eastern (MID) AF: 0.0692 AC: 57 AN: 824

European-Non Finnish (NFE) AF: 0.0343 AC: 4096 AN: 119418

Other (OTH) AF: 0.0418 AC: 445 AN: 10634

GnomAD4 genome AF: 0.0651 AC: 9905 AN: 152244 Hom.: 480 Cov.: 33 AF XY: 0.0643 AC XY: 4788 AN XY: 74434

African (AFR) AF: 0.126 AC: 5254 AN: 41538

American (AMR) AF: 0.0515 AC: 788 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3472

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5174

South Asian (SAS) AF: 0.111 AC: 536 AN: 4830

European-Finnish (FIN) AF: 0.0236 AC: 250 AN: 10598

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2674 AN: 68022

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0548 Hom.: 451

Bravo AF: 0.0667

Asia WGS AF: 0.0650 AC: 227 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.32
DANN	Benign	0.59
PhyloP100		-1.4
PromoterAI		0.034	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3136814; hg19: chr14-20923297;