NM_022767.4:c.44C>T

Variant names:

• chr15-88626253-C-T
• rs3743477
• NM_022767.4:c.44C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022767.4(AEN):​c.44C>T​(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 1,611,698 control chromosomes in the GnomAD database, including 2,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.072 (505 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2472 hom.)
• Consequence: AEN NM_022767.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.792
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014880002).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022767.4. 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
	AEN	NM_022767.4	MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 2 of 4	NP_073604.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AEN	ENST00000332810.4	TSL:1 MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 2 of 4	ENSP00000331944.3
	AEN	ENST00000557787.1	TSL:1	n.154C>T		non_coding_transcript_exon	Exon 2 of 2
	AEN	ENST00000937448.1		c.44C>T	p.Pro15Leu	missense	Exon 2 of 4	ENSP00000607507.1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10952 AN: 152228 Hom.: 499 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0518

Gnomad OTH AF: 0.0640

GnomAD2 exomes AF: 0.0582 AC: 14440 AN: 247938 AF XY: 0.0603

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.000656

Gnomad FIN exome AF: 0.0758

Gnomad NFE exome AF: 0.0515

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0524 AC: 76512 AN: 1459352 Hom.: 2472 Cov.: 31 AF XY: 0.0542 AC XY: 39331 AN XY: 725796

African (AFR) AF: 0.125 AC: 4184 AN: 33440

American (AMR) AF: 0.0342 AC: 1525 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1617 AN: 25970

East Asian (EAS) AF: 0.00131 AC: 52 AN: 39646

South Asian (SAS) AF: 0.0986 AC: 8485 AN: 86016

European-Finnish (FIN) AF: 0.0751 AC: 3961 AN: 52778

Middle Eastern (MID) AF: 0.0866 AC: 496 AN: 5730

European-Non Finnish (NFE) AF: 0.0474 AC: 52682 AN: 1110904

Other (OTH) AF: 0.0582 AC: 3510 AN: 60276

GnomAD4 genome AF: 0.0721 AC: 10977 AN: 152346 Hom.: 505 Cov.: 33 AF XY: 0.0727 AC XY: 5419 AN XY: 74496

African (AFR) AF: 0.123 AC: 5127 AN: 41568

American (AMR) AF: 0.0489 AC: 748 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0914 AC: 442 AN: 4834

European-Finnish (FIN) AF: 0.0664 AC: 705 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0518 AC: 3527 AN: 68038

Other (OTH) AF: 0.0681 AC: 144 AN: 2116

Alfa AF: 0.0537 Hom.: 678

Bravo AF: 0.0704

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.116 AC: 509

ESP6500EA AF: 0.0512 AC: 440

ExAC AF: 0.0603 AC: 7319

Asia WGS AF: 0.0640 AC: 222 AN: 3478

EpiCase AF: 0.0509

EpiControl AF: 0.0522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.79
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.0010	B
Vest4		0.067
MPC		0.084
ClinPred		0.0054	T
GERP RS		2.3
Varity_R		0.079
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743477; hg19: chr15-89169484; COSMIC: COSV107409477; COSMIC: COSV107409477;