15-43765434-C-CTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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: 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

GnomAD2 exomes AF: 0.000878 AC: 110 AN: 125316 AF XY: 0.000971

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.: 0 Cov.: 16 AF XY: 0.00174 AC XY: 914 AN XY: 524286

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

African (AFR) AF: 0.00208 AC: 49 AN: 23510

American (AMR) AF: 0.00119 AC: 40 AN: 33520

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 27 AN: 20488

East Asian (EAS) AF: 0.000628 AC: 21 AN: 33414

South Asian (SAS) AF: 0.000994 AC: 67 AN: 67434

European-Finnish (FIN) AF: 0.000578 AC: 26 AN: 44980

Middle Eastern (MID) AF: 0.000885 AC: 4 AN: 4520

European-Non Finnish (NFE) AF: 0.00209 AC: 1585 AN: 758232

Other (OTH) AF: 0.00172 AC: 76 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.

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

African (AFR) AF: 0.000617 AC: 24 AN: 38886

American (AMR) AF: 0.00 AC: 0 AN: 14058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64576

Other (OTH) AF: 0.00 AC: 0 AN: 1912

Alfa AF: 0.00184 Hom.: 4

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	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

Other links and lift over

dbSNP: rs747857317; hg19: chr15-44057632;