NM_152321.4:c.801G>C

Variant names:

• chr12-14914756-C-G
• rs138298248
• NM_152321.4:c.801G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152321.4(ERP27):​c.801G>C​(p.Lys267Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ERP27 NM_152321.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.409
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02360484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERP27	NM_152321.4	c.801G>C	p.Lys267Asn	missense_variant	Exon 7 of 7	ENST00000266397.7	NP_689534.1
ERP27	NM_001300784.2	c.498G>C	p.Lys166Asn	missense_variant	Exon 5 of 5		NP_001287713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERP27	ENST00000266397.7	c.801G>C	p.Lys267Asn	missense_variant	Exon 7 of 7	1	NM_152321.4	ENSP00000266397.2
ERP27	ENST00000540097.1	c.498G>C	p.Lys166Asn	missense_variant	Exon 5 of 5	2		ENSP00000440573.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00128

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 251122 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461456 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 727036

African (AFR) AF: 0.00125 AC: 42 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111816

Other (OTH) AF: 0.0000497 AC: 3 AN: 60378

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74500

African (AFR) AF: 0.00127 AC: 53 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.801G>C (p.K267N) alteration is located in exon 7 (coding exon 7) of the ERP27 gene. This alteration results from a G to C substitution at nucleotide position 801, causing the lysine (K) at amino acid position 267 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		-0.41
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.085
Sift	Benign	0.059	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.96	D;.
Vest4		0.19
MutPred		0.25		Loss of ubiquitination at K267 (P = 0.0039);.;
MVP		0.40
MPC		0.048
ClinPred		0.022	T
GERP RS		0.85
Varity_R		0.059
gMVP		0.32
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs138298248; hg19: chr12-15067690;