15-43761419-C-T

Variant names:

• chr15-43761419-C-T
• rs8040336
• NM_005313.5:c.365-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005313.5(PDIA3):​c.365-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,502,440 control chromosomes in the GnomAD database, including 206,733 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (16503 hom., cov: 31)
  • Exomes 𝑓: 0.52 (190230 hom.)
• Consequence: PDIA3 NM_005313.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006908
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0260

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-43761419-C-T is Benign according to our data. Variant chr15-43761419-C-T is described in ClinVar as [Benign]. Clinvar id is 1250388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA3	NM_005313.5	c.365-5C>T		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000300289.10	NP_005304.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA3	ENST00000300289.10	c.365-5C>T		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_005313.5	ENSP00000300289.5

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64140 AN: 151828 Hom.: 16500 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.500 AC: 117875 AN: 235742 AF XY: 0.506

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.524 AC: 707149 AN: 1350494 Hom.: 190230 Cov.: 19 AF XY: 0.522 AC XY: 353249 AN XY: 676734

Gnomad4 AFR exome AF: 0.103 AC: 3158 AN: 30634

Gnomad4 AMR exome AF: 0.554 AC: 21948 AN: 39586

Gnomad4 ASJ exome AF: 0.403 AC: 9990 AN: 24772

Gnomad4 EAS exome AF: 0.460 AC: 17946 AN: 39034

Gnomad4 SAS exome AF: 0.481 AC: 38888 AN: 80800

Gnomad4 FIN exome AF: 0.665 AC: 35305 AN: 53058

Gnomad4 NFE exome AF: 0.539 AC: 549993 AN: 1020640

Gnomad4 Remaining exome AF: 0.492 AC: 27796 AN: 56464

GnomAD4 genome AF: 0.422 AC: 64160 AN: 151946 Hom.: 16503 Cov.: 31 AF XY: 0.432 AC XY: 32042 AN XY: 74218

Gnomad4 AFR AF: 0.122 AC: 0.121757 AN: 0.121757

Gnomad4 AMR AF: 0.525 AC: 0.525318 AN: 0.525318

Gnomad4 ASJ AF: 0.407 AC: 0.407279 AN: 0.407279

Gnomad4 EAS AF: 0.431 AC: 0.430974 AN: 0.430974

Gnomad4 SAS AF: 0.496 AC: 0.495643 AN: 0.495643

Gnomad4 FIN AF: 0.680 AC: 0.679924 AN: 0.679924

Gnomad4 NFE AF: 0.536 AC: 0.536067 AN: 0.536067

Gnomad4 OTH AF: 0.437 AC: 0.437322 AN: 0.437322

Alfa AF: 0.496 Hom.: 41757

Bravo AF: 0.396

Asia WGS AF: 0.459 AC: 1594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PDIA3-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.8
DANN	Benign	0.46
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs8040336; hg19: chr15-44053617; COSMIC: COSV55855140; COSMIC: COSV55855140;