14-20454990-T-G

Variant names:

• chr14-20454990-T-G
• rs1760944
• ENST00000556252.1:n.64A>C

Variant summary

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

The ENST00000556252.1(OSGEP):​n.64A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 478,654 control chromosomes in the GnomAD database, including 90,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30163 hom., cov: 33)
  • Exomes 𝑓: 0.60 (60304 hom.)
• Consequence: OSGEP ENST00000556252.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.119
• Publications: 93 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-20454990-T-G is Benign according to our data. Variant chr14-20454990-T-G is described in ClinVar as Benign. ClinVar VariationId is 1282032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSGEP	NM_017807.4	c.-307A>C		upstream_gene_variant		ENST00000206542.9	NP_060277.1
APEX1	NM_001641.4	c.-473T>G		upstream_gene_variant		ENST00000216714.8	NP_001632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSGEP	ENST00000206542.9	c.-307A>C		upstream_gene_variant		1	NM_017807.4	ENSP00000206542.4
APEX1	ENST00000216714.8	c.-473T>G		upstream_gene_variant		1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95098 AN: 151980 Hom.: 30119 Cov.: 33

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.637

GnomAD4 exome AF: 0.604 AC: 197113 AN: 326556 Hom.: 60304 Cov.: 0 AF XY: 0.602 AC XY: 102839 AN XY: 170924

African (AFR) AF: 0.704 AC: 6834 AN: 9708

American (AMR) AF: 0.488 AC: 5734 AN: 11760

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 6702 AN: 10234

East Asian (EAS) AF: 0.502 AC: 10772 AN: 21460

South Asian (SAS) AF: 0.582 AC: 20181 AN: 34648

European-Finnish (FIN) AF: 0.689 AC: 14621 AN: 21216

Middle Eastern (MID) AF: 0.697 AC: 1020 AN: 1464

European-Non Finnish (NFE) AF: 0.606 AC: 119579 AN: 197174

Other (OTH) AF: 0.618 AC: 11670 AN: 18892

GnomAD4 genome AF: 0.626 AC: 95207 AN: 152098 Hom.: 30163 Cov.: 33 AF XY: 0.628 AC XY: 46654 AN XY: 74318

African (AFR) AF: 0.702 AC: 29153 AN: 41512

American (AMR) AF: 0.528 AC: 8066 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2225 AN: 3472

East Asian (EAS) AF: 0.446 AC: 2300 AN: 5156

South Asian (SAS) AF: 0.565 AC: 2726 AN: 4822

European-Finnish (FIN) AF: 0.708 AC: 7477 AN: 10564

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41154 AN: 67974

Other (OTH) AF: 0.637 AC: 1342 AN: 2108

Alfa AF: 0.611 Hom.: 37446

Bravo AF: 0.615

Asia WGS AF: 0.547 AC: 1904 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 13, 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	7.1
DANN	Benign	0.59
PhyloP100		0.12
PromoterAI		-0.015	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

dbSNP: rs1760944; hg19: chr14-20923149;