chr3-123092356-G-T

Position:

chr3-123092356-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006810.4(PDIA5):c.171G>T(p.Glu57Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign 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: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PDIA5
NM_006810.4 missense, splice_region

Scores

Splicing: ADA: 0.00005739

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.134

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11111772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDIA5	NM_006810.4 linkuse as main transcript	c.171G>T	p.Glu57Asp	missense_variant, splice_region_variant	3/17	ENST00000316218.12
PDIA5	NR_028444.2 linkuse as main transcript	n.311G>T		splice_region_variant, non_coding_transcript_exon_variant	3/16
PDIA5	XR_007095629.1 linkuse as main transcript	n.311G>T		splice_region_variant, non_coding_transcript_exon_variant	3/14
PDIA5	XR_007095630.1 linkuse as main transcript	n.311G>T		splice_region_variant, non_coding_transcript_exon_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA5	ENST00000316218.12 linkuse as main transcript	c.171G>T	p.Glu57Asp	missense_variant, splice_region_variant	3/17	1	NM_006810.4	P1	Q14554-1
PDIA5	ENST00000489923.5 linkuse as main transcript	c.171G>T	p.Glu57Asp	missense_variant, splice_region_variant, NMD_transcript_variant	3/16	1			Q14554-2
PDIA5	ENST00000484644.5 linkuse as main transcript	c.-118G>T		splice_region_variant, 5_prime_UTR_variant	3/6	5
PDIA5	ENST00000495004.1 linkuse as main transcript	n.190G>T		splice_region_variant, non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251248

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000685

AC:

AN:

1460244

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 19, 2024

The c.171G>T (p.E57D) alteration is located in exon 3 (coding exon 3) of the PDIA5 gene. This alteration results from a G to T substitution at nucleotide position 171, causing the glutamic acid (E) at amino acid position 57 to be replaced by an aspartic acid (D). 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

-0.27

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.022

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.75

M_CAP

Benign

0.0027

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.66

REVEL

Benign

0.12

Sift

Benign

0.56

Sift4G

Benign

0.62

Polyphen

0.0010

Vest4

0.26

MutPred

0.55

Loss of sheet (P = 0.0037);

MVP

0.26

MPC

0.064

ClinPred

0.054

GERP RS

0.71

Varity_R

0.14

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000057

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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