chr3-123106750-C-A

Position:

chr3-123106750-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006810.4(PDIA5):c.389C>A(p.Ser130Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000374 in 1,605,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PDIA5
NM_006810.4 missense, splice_region

Scores

Splicing: ADA: 0.5298

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Variant links:

Genes affected

PDIA5 (HGNC:24811): (protein disulfide isomerase family A member 5) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, three catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. The N-terminal TRX-like domain is the primary binding site for the major ER chaperone calreticulin and possibly other proteins and substrates as well. Alternative splicing results in multiple protein- and non-protein-coding transcript variants. [provided by RefSeq, Dec 2016]

PDIA5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDIA5	NM_006810.4 linkuse as main transcript	c.389C>A	p.Ser130Tyr	missense_variant, splice_region_variant	6/17	ENST00000316218.12
PDIA5	NR_028444.2 linkuse as main transcript	n.529C>A		splice_region_variant, non_coding_transcript_exon_variant	6/16
PDIA5	XR_007095629.1 linkuse as main transcript	n.529C>A		splice_region_variant, non_coding_transcript_exon_variant	6/14
PDIA5	XR_007095630.1 linkuse as main transcript	n.529C>A		splice_region_variant, non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA5	ENST00000316218.12 linkuse as main transcript	c.389C>A	p.Ser130Tyr	missense_variant, splice_region_variant	6/17	1	NM_006810.4	P1	Q14554-1
PDIA5	ENST00000489923.5 linkuse as main transcript	c.389C>A	p.Ser130Tyr	missense_variant, splice_region_variant, NMD_transcript_variant	6/16	1			Q14554-2
PDIA5	ENST00000484644.5 linkuse as main transcript	c.101C>A	p.Ser34Tyr	missense_variant, splice_region_variant	6/6	5
PDIA5	ENST00000495004.1 linkuse as main transcript	n.408C>A		splice_region_variant, non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453102

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.389C>A (p.S130Y) alteration is located in exon 6 (coding exon 6) of the PDIA5 gene. This alteration results from a C to A substitution at nucleotide position 389, causing the serine (S) at amino acid position 130 to be replaced by a tyrosine (Y). 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

0.95

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.74

D;D

MetaSVM

Benign

-0.80

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.51

Loss of catalytic residue at S130 (P = 0.0729);.;

MVP

0.40

MPC

0.40

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over