dbSNP rs200754170: ERP27:p.Phe156Leu (chr12-14917286-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152321.4(ERP27):c.468C>G(p.Phe156Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

ERP27
NM_152321.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.558

Publications

2 publications found

Variant links:

Genes affected

ERP27 (HGNC:26495): (endoplasmic reticulum protein 27) This gene encodes a noncatalytic member of the protein disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins. The canonical protein has an N-terminal signal sequence, two thioredoxin (TRX)-like domains and a C-terminal ER-retention sequence. Alternative splicing results in multiple transcript variants encoding distinct isoforms; some of which lack domains present in the canonical protein. [provided by RefSeq, Dec 2016]

ERP27 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14151704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERP27	NM_152321.4 link	c.468C>G	p.Phe156Leu	missense_variant	Exon 5 of 7	ENST00000266397.7	NP_689534.1	Q96DN0
ERP27	NM_001300784.2 link	c.165C>G	p.Phe55Leu	missense_variant	Exon 3 of 5		NP_001287713.1	Q96DN0F5GYS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERP27	ENST00000266397.7 link	c.468C>G	p.Phe156Leu	missense_variant	Exon 5 of 7	1	NM_152321.4	ENSP00000266397.2	Q96DN0
ERP27	ENST00000540097.1 link	c.165C>G	p.Phe55Leu	missense_variant	Exon 3 of 5	2		ENSP00000440573.1	F5GYS6
ERP27	ENST00000544881.1 link	n.-7C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000247

AC:

AN:

251450

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000338

AC:

494

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000407

AC:

453

AN:

1111982

Other (OTH)

AF:

0.000248

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.468C>G (p.F156L) alteration is located in exon 5 (coding exon 5) of the ERP27 gene. This alteration results from a C to G substitution at nucleotide position 468, causing the phenylalanine (F) at amino acid position 156 to be replaced by a leucine (L). 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

0.83

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.56

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.21

Sift

Benign

0.27

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.046

B;.

Vest4

0.46

MutPred

0.85

Loss of catalytic residue at F156 (P = 0.154);.;

MVP

0.23

MPC

0.060

ClinPred

0.064

GERP RS

1.0

Varity_R

0.64

gMVP

0.86

Mutation Taster

=59/41

polymorphism

(source)

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

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rs200754170

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over