Variant 3-123106834-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006810.4(PDIA5):c.473G>T(p.Ser158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S158G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDIA5
NM_006810.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.253

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=0.20114398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDIA5	NM_006810.4 linkuse as main transcript	c.473G>T	p.Ser158Ile	missense_variant	6/17	ENST00000316218.12
PDIA5	NR_028444.2 linkuse as main transcript	n.613G>T		non_coding_transcript_exon_variant	6/16
PDIA5	XR_007095629.1 linkuse as main transcript	n.613G>T		non_coding_transcript_exon_variant	6/14
PDIA5	XR_007095630.1 linkuse as main transcript	n.613G>T		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.473G>T	p.Ser158Ile	missense_variant	6/17	1	NM_006810.4	P1	Q14554-1
PDIA5	ENST00000489923.5 linkuse as main transcript	c.473G>T	p.Ser158Ile	missense_variant, NMD_transcript_variant	6/16	1			Q14554-2
PDIA5	ENST00000484644.5 linkuse as main transcript	c.185G>T	p.Ser62Ile	missense_variant	6/6	5
PDIA5	ENST00000495004.1 linkuse as main transcript	n.492G>T		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1451906

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

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

Sep 26, 2023

The c.473G>T (p.S158I) alteration is located in exon 6 (coding exon 6) of the PDIA5 gene. This alteration results from a G to T substitution at nucleotide position 473, causing the serine (S) at amino acid position 158 to be replaced by an isoleucine (I). 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

0.28

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.20

Sift

Benign

0.033

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.013

B;.

Vest4

0.43

MVP

0.21

MPC

0.11

ClinPred

0.92

GERP RS

1.4

Varity_R

0.22

gMVP

0.58

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

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