rs12004

Positions:

• chr22-38481456-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006855.4(KDELR3):​c.596T>G​(p.Val199Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,613,664 control chromosomes in the GnomAD database, including 71,264 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5909 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65355 hom.)
• Consequence: KDELR3 NM_006855.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

Genes affected

KDELR3 (HGNC:6306): (KDEL endoplasmic reticulum protein retention receptor 3) This gene encodes a member of the KDEL endoplasmic reticulum protein retention receptor family. Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells, and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes, and binds the tetrapeptide-containing protein, and returns it to the ER. In yeast, the sorting receptor encoded by a single gene, ERD2, is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. KDELR3 was the third member of the family to be identified. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016810596).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDELR3	NM_006855.4	c.596T>G	p.Val199Gly	missense_variant	4/5	ENST00000216014.9
KDELR3	NM_016657.3	c.596T>G	p.Val199Gly	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDELR3	ENST00000216014.9	c.596T>G	p.Val199Gly	missense_variant	4/5	1	NM_006855.4	P1
KDELR3	ENST00000409006.3	c.596T>G	p.Val199Gly	missense_variant	4/4	1
KDELR3	ENST00000471268.1	n.535T>G		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41282 AN: 151926 Hom.: 5903 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.268

GnomAD3 exomes AF: 0.288 AC: 72342 AN: 251260 Hom.: 10868 AF XY: 0.291 AC XY: 39591 AN XY: 135820

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.275

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.296 AC: 432963 AN: 1461620 Hom.: 65355 Cov.: 37 AF XY: 0.296 AC XY: 215270 AN XY: 727098

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.272 AC: 41316 AN: 152044 Hom.: 5909 Cov.: 32 AF XY: 0.273 AC XY: 20313 AN XY: 74306

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.273

Alfa AF: 0.295 Hom.: 16389

Bravo AF: 0.257

TwinsUK AF: 0.296 AC: 1097

ALSPAC AF: 0.311 AC: 1198

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.306 AC: 2634

ExAC AF: 0.288 AC: 35011

Asia WGS AF: 0.309 AC: 1076 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.294

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	2.1e-10	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.13	T;D
Polyphen		0.36	B;P
Vest4		0.48
MPC		0.53
ClinPred		0.048	T
GERP RS		4.7
Varity_R		0.65
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs12004; hg19: chr22-38877461; COSMIC: COSV53246548; COSMIC: COSV53246548;