ENST00000556252.1:n.64A>G

Variant names:

• chr14-20454990-T-C
• rs1760944
• ENST00000923861.1:c.-307A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000556252.1(OSGEP):​n.64A>G 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 0.00000658 in 152,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OSGEP ENST00000556252.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000556252.1. 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
	OSGEP	NM_017807.4	MANE Select	c.-307A>G		upstream_gene	N/A	NP_060277.1	Q9NPF4
	APEX1	NM_001641.4	MANE Select	c.-473T>C		upstream_gene	N/A	NP_001632.2
	APEX1	NM_001244249.2		c.-468T>C		upstream_gene	N/A	NP_001231178.1	Q5TZP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSGEP	ENST00000923861.1		c.-307A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000593920.1
	OSGEP	ENST00000923861.1		c.-307A>G		5_prime_UTR	Exon 1 of 10	ENSP00000593920.1
	APEX1	ENST00000956430.1		c.-69+403T>C		intron	N/A	ENSP00000626489.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 327492 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 171402

African (AFR) AF: 0.00 AC: 0 AN: 9728

American (AMR) AF: 0.00 AC: 0 AN: 11806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10260

East Asian (EAS) AF: 0.00 AC: 0 AN: 21542

South Asian (SAS) AF: 0.00 AC: 0 AN: 34694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1466

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 197738

Other (OTH) AF: 0.00 AC: 0 AN: 18954

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

African (AFR) AF: 0.0000242 AC: 1 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 37446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.4
DANN	Benign	0.77
PhyloP100		0.12
PromoterAI		-0.024	Neutral

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;