chr15-43761436-G-A
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005313.5(PDIA3):c.377G>A(p.Ser126Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,579,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
PDIA3
NM_005313.5 missense
NM_005313.5 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 5.71
Genes affected
PDIA3 (HGNC:4606): (protein disulfide isomerase family A member 3) This gene encodes a protein of the endoplasmic reticulum that interacts with lectin chaperones calreticulin and calnexin to modulate folding of newly synthesized glycoproteins. The protein was once thought to be a phospholipase; however, it has been demonstrated that the protein actually has protein disulfide isomerase activity. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates. This protein also functions as a molecular chaperone that prevents the formation of protein aggregates. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2634139).
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDIA3 | NM_005313.5 | c.377G>A | p.Ser126Asn | missense_variant | 4/13 | ENST00000300289.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDIA3 | ENST00000300289.10 | c.377G>A | p.Ser126Asn | missense_variant | 4/13 | 1 | NM_005313.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152076Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000209 AC: 5AN: 239780Hom.: 0 AF XY: 0.0000231 AC XY: 3AN XY: 129720
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GnomAD4 exome AF: 0.0000595 AC: 85AN: 1427754Hom.: 0 Cov.: 25 AF XY: 0.0000632 AC XY: 45AN XY: 711586
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152076Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74270
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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 16, 2021 | The c.377G>A (p.S126N) alteration is located in exon 4 (coding exon 4) of the PDIA3 gene. This alteration results from a G to A substitution at nucleotide position 377, causing the serine (S) at amino acid position 126 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of disorder (P = 0.0838);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at