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
• Publications: 22 publications found

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 VariationId 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

African (AFR) AF: 0.103 AC: 3158 AN: 30634

American (AMR) AF: 0.554 AC: 21948 AN: 39586

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 9990 AN: 24772

East Asian (EAS) AF: 0.460 AC: 17946 AN: 39034

South Asian (SAS) AF: 0.481 AC: 38888 AN: 80800

European-Finnish (FIN) AF: 0.665 AC: 35305 AN: 53058

Middle Eastern (MID) AF: 0.386 AC: 2125 AN: 5506

European-Non Finnish (NFE) AF: 0.539 AC: 549993 AN: 1020640

Other (OTH) 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

African (AFR) AF: 0.122 AC: 5049 AN: 41468

American (AMR) AF: 0.525 AC: 8009 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1410 AN: 3462

East Asian (EAS) AF: 0.431 AC: 2229 AN: 5172

South Asian (SAS) AF: 0.496 AC: 2389 AN: 4820

European-Finnish (FIN) AF: 0.680 AC: 7146 AN: 10510

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36429 AN: 67956

Other (OTH) AF: 0.437 AC: 921 AN: 2106

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
PhyloP100		-0.026
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

Other links and lift over

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