Genetic Variant PDIA3:c.603-5_603-4dupTT (chr15-43765434-C-CTT) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_005313.5(PDIA3):c.603-5_603-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,172,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 0 hom. )

Consequence

PDIA3
NM_005313.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.737

Publications

0 publications found

Variant links:

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]

PDIA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 15-43765434-C-CTT is Benign according to our data. Variant chr15-43765434-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3055506.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 24 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.603-5_603-4dupTT		splice_region intron	N/A	NP_005304.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDIA3	ENST00000300289.10	TSL:1 MANE Select	c.603-5_603-4dupTT	splice_region intron	N/A	ENSP00000300289.5	P30101
PDIA3	ENST00000688851.1		c.603-5_603-4dupTT	splice_region intron	N/A	ENSP00000510205.1	A0A8I5KT88
PDIA3	ENST00000891522.1		c.585-5_585-4dupTT	splice_region intron	N/A	ENSP00000561581.1

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

141698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000878

AC:

110

AN:

125316

AF XY:

0.000971

show subpopulations

Gnomad AFR exome

AF:

0.00184

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.00152

Gnomad EAS exome

AF:

0.000740

Gnomad FIN exome

AF:

0.000192

Gnomad NFE exome

AF:

0.000554

Gnomad OTH exome

AF:

0.00202

GnomAD4 exome

AF:

0.00184

AC:

1895

AN:

1030368

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

914

AN XY:

524286

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00208

AC:

AN:

23510

American (AMR)

AF:

0.00119

AC:

AN:

33520

Ashkenazi Jewish (ASJ)

AF:

0.00132

AC:

AN:

20488

East Asian (EAS)

AF:

0.000628

AC:

AN:

33414

South Asian (SAS)

AF:

0.000994

AC:

AN:

67434

European-Finnish (FIN)

AF:

0.000578

AC:

AN:

44980

Middle Eastern (MID)

AF:

0.000885

AC:

AN:

4520

European-Non Finnish (NFE)

AF:

0.00209

AC:

1585

AN:

758232

Other (OTH)

AF:

0.00172

AC:

AN:

44270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.255

Heterozygous variant carriers

246

491

737

982

1228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000169

AC:

AN:

141718

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

AN XY:

68742

show subpopulations

African (AFR)

AF:

0.000617

AC:

AN:

38886

American (AMR)

AF:

0.00

AC:

AN:

14058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3304

East Asian (EAS)

AF:

0.00

AC:

AN:

4908

South Asian (SAS)

AF:

0.00

AC:

AN:

4484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64576

Other (OTH)

AF:

0.00

AC:

AN:

1912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00184

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PDIA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over