14-20457272-GGG-CGT

Variant names:

• chr14-20457272-GGG-CGT
• NM_001641.4:c.721_723delGGGinsCGT
• APEX1 p.Gly241Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001641.4(APEX1):​c.721_723delGGGinsCGT​(p.Gly241Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• Publications: 0 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]

APEX1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001641.4. 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
	APEX1	NM_001641.4	MANE Select	c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	NP_001632.2
	APEX1	NM_001244249.2		c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	NP_001231178.1	Q5TZP7
	APEX1	NM_080648.3		c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	NP_542379.1	Q5TZP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX1	ENST00000216714.8	TSL:1 MANE Select	c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	ENSP00000216714.3	P27695
	APEX1	ENST00000398030.8	TSL:1	c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	ENSP00000381111.4	P27695
	APEX1	ENST00000555414.5	TSL:1	c.721_723delGGGinsCGT	p.Gly241Arg	missense	N/A	ENSP00000451979.1	P27695

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-20925431;