12-14917263-A-T

Position:

• chr12-14917263-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152321.4(ERP27):​c.491T>A​(p.Leu164His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ERP27 NM_152321.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERP27	NM_152321.4	c.491T>A	p.Leu164His	missense_variant	5/7	ENST00000266397.7
ERP27	NM_001300784.2	c.188T>A	p.Leu63His	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERP27	ENST00000266397.7	c.491T>A	p.Leu164His	missense_variant	5/7	1	NM_152321.4	P1
ERP27	ENST00000540097.1	c.188T>A	p.Leu63His	missense_variant	3/5	2
ERP27	ENST00000544881.1	n.17T>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 29, 2021

The c.491T>A (p.L164H) alteration is located in exon 5 (coding exon 5) of the ERP27 gene. This alteration results from a T to A substitution at nucleotide position 491, causing the leucine (L) at amino acid position 164 to be replaced by a histidine (H). 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	0.80
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.65		Loss of stability (P = 0.0189);.;
MVP		0.55
MPC		0.32
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr12-15070197;