chr12-112019778-T-C

Variant names:

• chr12-112019778-T-C
• NM_006817.4:c.167T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006817.4(ERP29):​c.167T>C​(p.Val56Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERP29 NM_006817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50
• Publications: 0 publications found

Genes affected

ERP29 (HGNC:13799): (endoplasmic reticulum protein 29) This gene encodes a protein which localizes to the lumen of the endoplasmic reticulum (ER). It is a member of the protein disulfide isomerase (PDI) protein family but lacks an active thioredoxin motif, suggesting that this protein does not function as a disulfide isomerase. The canonical protein dimerizes and is thought to play a role in the processing of secretory proteins within the ER. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

LOC124903021 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERP29	NM_006817.4	c.167T>C	p.Val56Ala	missense_variant	Exon 2 of 3	ENST00000261735.4	NP_006808.1
LOC124903021	XR_007063464.1	n.1713A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ERP29	NM_001034025.2	c.145-2372T>C		intron_variant	Intron 1 of 1		NP_001029197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERP29	ENST00000261735.4	c.167T>C	p.Val56Ala	missense_variant	Exon 2 of 3	1	NM_006817.4	ENSP00000261735.3
ERP29	ENST00000552052.1	c.224T>C	p.Val75Ala	missense_variant	Exon 2 of 2	3		ENSP00000447472.1
ERP29	ENST00000546477.1	c.-137T>C		5_prime_UTR_variant	Exon 2 of 3	3		ENSP00000449018.1
ERP29	ENST00000455836.1	c.145-2372T>C		intron_variant	Intron 1 of 1	2		ENSP00000412083.1

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

Nov 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.167T>C (p.V56A) alteration is located in exon 2 (coding exon 2) of the ERP29 gene. This alteration results from a T to C substitution at nucleotide position 167, causing the valine (V) at amino acid position 56 to be replaced by an alanine (A). 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	0.66
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Benign	0.37	T
Sift4G	Benign	0.41	T
Polyphen		0.67	P
Vest4		0.88
MutPred		0.55		Loss of stability (P = 0.0295);
MVP		0.56
MPC		0.65
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.71
Mutation Taster		=39/61	disease causing

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

hg19: chr12-112457582;