15-88626396-C-T

Position:

• chr15-88626396-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022767.4(AEN):​c.187C>T​(p.Pro63Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AEN NM_022767.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983

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]

AEN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05766067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AEN	NM_022767.4	c.187C>T	p.Pro63Ser	missense_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.187C>T	p.Pro63Ser	missense_variant	2/4	1	NM_022767.4	ENSP00000331944.3
AEN	ENST00000557787.1	n.297C>T		non_coding_transcript_exon_variant	2/2	1
AEN	ENST00000559528.1	c.187C>T	p.Pro63Ser	missense_variant	2/2	2		ENSP00000453631.1
AEN	ENST00000558327.1	n.668C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.187C>T (p.P63S) alteration is located in exon 2 (coding exon 1) of the AEN gene. This alteration results from a C to T substitution at nucleotide position 187, causing the proline (P) at amino acid position 63 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.050
Sift	Benign	0.55	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.023	B;.
Vest4		0.16
MutPred		0.20		Gain of phosphorylation at P63 (P = 0.0145);Gain of phosphorylation at P63 (P = 0.0145);
MVP		0.088
MPC		0.083
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.067
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-89169627;