rs3743476

Positions:

• chr15-88626383-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_022767.4(AEN):​c.174A>G​(p.Glu58Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,611,358 control chromosomes in the GnomAD database, including 89,739 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 0.27 (6747 hom., cov: 34)
  • Exomes 𝑓: 0.33 (82992 hom.)
• Consequence: AEN NM_022767.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150

Genes affected

AEN (HGNC:25722): (apoptosis enhancing nuclease) Enables exonuclease activity. Involved in intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator and response to ionizing radiation. Located in nuclear membrane; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AEN	NM_022767.4	c.174A>G	p.Glu58Glu	synonymous_variant	2/4	ENST00000332810.4	NP_073604.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AEN	ENST00000332810.4	c.174A>G	p.Glu58Glu	synonymous_variant	2/4	1	NM_022767.4	ENSP00000331944.3
AEN	ENST00000557787.1	n.284A>G		non_coding_transcript_exon_variant	2/2	1
AEN	ENST00000559528.1	c.174A>G	p.Glu58Glu	synonymous_variant	2/2	2		ENSP00000453631.1
AEN	ENST00000558327.1	n.655A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41171 AN: 152072 Hom.: 6748 Cov.: 34

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.283 AC: 69161 AN: 244174 Hom.: 11001 AF XY: 0.290 AC XY: 38362 AN XY: 132392

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.329 AC: 480373 AN: 1459168 Hom.: 82992 Cov.: 80 AF XY: 0.327 AC XY: 237334 AN XY: 725666

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.271 AC: 41175 AN: 152190 Hom.: 6747 Cov.: 34 AF XY: 0.273 AC XY: 20322 AN XY: 74400

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.281

Alfa AF: 0.317 Hom.: 3778

Bravo AF: 0.246

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743476; hg19: chr15-89169614; COSMIC: COSV60428832; COSMIC: COSV60428832;