rs78540343

Variant names:

• chr15-43753815-C-T
• rs78540343
• NM_005313.5:c.168-9C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005313.5(PDIA3):​c.168-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,596,862 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (47 hom.)
• Consequence: PDIA3 NM_005313.5 intron
• Scores: Splicing: ADA: 0.00001375
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.330
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 15-43753815-C-T is Benign according to our data. Variant chr15-43753815-C-T is described in ClinVar as Benign. ClinVar VariationId is 714532.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1865/152156) while in subpopulation AFR AF = 0.0426 (1768/41496). AF 95% confidence interval is 0.041. There are 38 homozygotes in GnomAd4. There are 898 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1865 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005313.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA3	NM_005313.5	MANE Select	c.168-9C>T		intron	N/A	NP_005304.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA3	ENST00000300289.10	TSL:1 MANE Select	c.168-9C>T		intron	N/A	ENSP00000300289.5	P30101
	PDIA3	ENST00000688851.1		c.168-9C>T		intron	N/A	ENSP00000510205.1	A0A8I5KT88
	PDIA3	ENST00000891522.1		c.168-9C>T		intron	N/A	ENSP00000561581.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1842 AN: 152038 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00317 AC: 783 AN: 247232 AF XY: 0.00231

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00119 AC: 1726 AN: 1444706 Hom.: 47 Cov.: 27 AF XY: 0.00105 AC XY: 753 AN XY: 719480

African (AFR) AF: 0.0417 AC: 1375 AN: 32974

American (AMR) AF: 0.00226 AC: 99 AN: 43748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.000236 AC: 20 AN: 84614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5714

European-Non Finnish (NFE) AF: 0.0000255 AC: 28 AN: 1099130

Other (OTH) AF: 0.00335 AC: 200 AN: 59784

GnomAD4 genome AF: 0.0123 AC: 1865 AN: 152156 Hom.: 38 Cov.: 31 AF XY: 0.0121 AC XY: 898 AN XY: 74386

African (AFR) AF: 0.0426 AC: 1768 AN: 41496

American (AMR) AF: 0.00510 AC: 78 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00554 Hom.: 8

Bravo AF: 0.0132

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PDIA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.8
DANN	Benign	0.64
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
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: rs78540343; hg19: chr15-44046013;