chr14-20456930-C-T

Variant names:

• chr14-20456930-C-T
• rs3136819
• NM_001641.4:c.440-61C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001641.4(APEX1):​c.440-61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,603,288 control chromosomes in the GnomAD database, including 37 homozygotes. 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 0.0091 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (16 hom.)
• Consequence: APEX1 NM_001641.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.06
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0091 (1386/152378) while in subpopulation AFR AF = 0.0317 (1319/41582). AF 95% confidence interval is 0.0303. There are 21 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1386 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX1	NM_001641.4	MANE Select	c.440-61C>T		intron	N/A	NP_001632.2
	APEX1	NM_001244249.2		c.440-61C>T		intron	N/A	NP_001231178.1
	APEX1	NM_080648.3		c.440-61C>T		intron	N/A	NP_542379.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX1	ENST00000216714.8	TSL:1 MANE Select	c.440-61C>T		intron	N/A	ENSP00000216714.3
	APEX1	ENST00000398030.8	TSL:1	c.440-61C>T		intron	N/A	ENSP00000381111.4
	APEX1	ENST00000555414.5	TSL:1	c.440-61C>T		intron	N/A	ENSP00000451979.1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1378 AN: 152260 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.000897 AC: 1302 AN: 1450910 Hom.: 16 Cov.: 32 AF XY: 0.000791 AC XY: 570 AN XY: 721024

African (AFR) AF: 0.0320 AC: 1066 AN: 33324

American (AMR) AF: 0.00167 AC: 71 AN: 42598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.0000822 AC: 7 AN: 85192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52736

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.0000398 AC: 44 AN: 1105850

Other (OTH) AF: 0.00178 AC: 107 AN: 60016

GnomAD4 genome AF: 0.00910 AC: 1386 AN: 152378 Hom.: 21 Cov.: 33 AF XY: 0.00871 AC XY: 649 AN XY: 74518

African (AFR) AF: 0.0317 AC: 1319 AN: 41582

American (AMR) AF: 0.00274 AC: 42 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68046

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00784 Hom.: 2

Bravo AF: 0.0102

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.028
DANN	Benign	0.63
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism

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: rs3136819; hg19: chr14-20925089;