NM_005313.5:c.603-5_603-4dupTT

Variant names:

• chr15-43765434-C-CTT
• rs747857317
• NM_005313.5:c.603-5_603-4dupTT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.737

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

Verdict is Likely_benign. Variant got -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 id is 3055506.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA3	NM_005313.5	c.603-5_603-4dupTT		splice_region_variant, intron_variant	Intron 5 of 12	ENST00000300289.10	NP_005304.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA3	ENST00000300289.10	c.603-5_603-4dupTT		splice_region_variant, intron_variant	Intron 5 of 12	1	NM_005313.5	ENSP00000300289.5

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 24 AN: 141698 Hom.: 0 Cov.: 31

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

GnomAD4 exome AF: 0.00184 AC: 1895 AN: 1030368 Hom.: 0 Cov.: 16 AF XY: 0.00174 AC XY: 914 AN XY: 524286

Gnomad4 AFR exome AF: 0.00208

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.000628

Gnomad4 SAS exome AF: 0.000994

Gnomad4 FIN exome AF: 0.000578

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000169 AC: 24 AN: 141718 Hom.: 0 Cov.: 31 AF XY: 0.000160 AC XY: 11 AN XY: 68742

Gnomad4 AFR AF: 0.000617

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PDIA3-related disorder Benign:1

Aug 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs747857317; hg19: chr15-44057632;