1-160213167-C-T

Variant names:

• chr1-160213167-C-T
• rs1654945451
• NM_003768.5:c.230C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003768.5(PEA15):​c.230C>T​(p.Thr77Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PEA15 NM_003768.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

Genes affected

PEA15 (HGNC:8822): (proliferation and apoptosis adaptor protein 15) This gene encodes a death effector domain-containing protein that functions as a negative regulator of apoptosis. The encoded protein is an endogenous substrate for protein kinase C. This protein is also overexpressed in type 2 diabetes mellitus, where it may contribute to insulin resistance in glucose uptake. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEA15	NM_003768.5	c.230C>T	p.Thr77Ile	missense_variant	Exon 3 of 4	ENST00000360472.9	NP_003759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEA15	ENST00000360472.9	c.230C>T	p.Thr77Ile	missense_variant	Exon 3 of 4	1	NM_003768.5	ENSP00000353660.5
PEA15	ENST00000368076.1	c.293C>T	p.Thr98Ile	missense_variant	Exon 5 of 6	2		ENSP00000357055.1
PEA15	ENST00000368077.5	c.164C>T	p.Thr55Ile	missense_variant	Exon 3 of 4	2		ENSP00000357056.1
PEA15	ENST00000488858.1	n.260C>T		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230C>T (p.T77I) alteration is located in exon 3 (coding exon 2) of the PEA15 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the threonine (T) at amino acid position 77 to be replaced by an isoleucine (I). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.62
MutPred		0.67		.;.;Loss of sheet (P = 0.0817);
MVP		0.86
MPC		2.5
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.60
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1654945451; hg19: chr1-160182957;