rs4677994

Variant names:

• chr3-123095206-C-T
• rs4677994
• NM_006810.4:c.257+2764C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006810.4(PDIA5):​c.257+2764C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0688 in 152,182 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.069 (507 hom., cov: 32)
• Consequence: PDIA5 NM_006810.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 5 publications found

Genes affected

PDIA5 (HGNC:24811): (protein disulfide isomerase family A member 5) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, three catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. The N-terminal TRX-like domain is the primary binding site for the major ER chaperone calreticulin and possibly other proteins and substrates as well. Alternative splicing results in multiple protein- and non-protein-coding transcript variants. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA5	NM_006810.4	c.257+2764C>T		intron_variant	Intron 3 of 16	ENST00000316218.12	NP_006801.1
PDIA5	NR_028444.2	n.397+2764C>T		intron_variant	Intron 3 of 15
PDIA5	XR_007095629.1	n.397+2764C>T		intron_variant	Intron 3 of 13
PDIA5	XR_007095630.1	n.397+2764C>T		intron_variant	Intron 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA5	ENST00000316218.12	c.257+2764C>T		intron_variant	Intron 3 of 16	1	NM_006810.4	ENSP00000323313.7
PDIA5	ENST00000489923.5	n.257+2764C>T		intron_variant	Intron 3 of 15	1		ENSP00000417520.1
PDIA5	ENST00000484644.5	c.-32+2764C>T		intron_variant	Intron 3 of 5	5		ENSP00000419946.1
PDIA5	ENST00000495004.1	n.276+2764C>T		intron_variant	Intron 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10476 AN: 152064 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0790

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.0746

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0967

Gnomad OTH AF: 0.0940

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0688 AC: 10475 AN: 152182 Hom.: 507 Cov.: 32 AF XY: 0.0695 AC XY: 5172 AN XY: 74392

African (AFR) AF: 0.0165 AC: 684 AN: 41526

American (AMR) AF: 0.0789 AC: 1206 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 423 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0995 AC: 480 AN: 4826

European-Finnish (FIN) AF: 0.0746 AC: 789 AN: 10578

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0967 AC: 6576 AN: 68004

Other (OTH) AF: 0.0920 AC: 194 AN: 2108

Alfa AF: 0.0915 Hom.: 370

Bravo AF: 0.0646

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.62
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4677994; hg19: chr3-122814053;