rs12004

Variant names:

• chr22-38481456-T-G
• rs12004
• NM_006855.4:c.596T>G

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 49 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006855.4. 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
	KDELR3	NM_006855.4	MANE Select	c.596T>G	p.Val199Gly	missense	Exon 4 of 5	NP_006846.1	O43731-1
	KDELR3	NM_016657.3		c.596T>G	p.Val199Gly	missense	Exon 4 of 4	NP_057839.1	O43731-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDELR3	ENST00000216014.9	TSL:1 MANE Select	c.596T>G	p.Val199Gly	missense	Exon 4 of 5	ENSP00000216014.4	O43731-1
	KDELR3	ENST00000409006.3	TSL:1	c.596T>G	p.Val199Gly	missense	Exon 4 of 4	ENSP00000386918.3	O43731-2
	KDELR3	ENST00000943543.1		c.677T>G	p.Val226Gly	missense	Exon 4 of 5	ENSP00000613602.1

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

GnomAD2 exomes AF: 0.288 AC: 72342 AN: 251260 AF XY: 0.291

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 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

African (AFR) AF: 0.187 AC: 6248 AN: 33474

American (AMR) AF: 0.215 AC: 9599 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7678 AN: 26136

East Asian (EAS) AF: 0.379 AC: 15064 AN: 39700

South Asian (SAS) AF: 0.275 AC: 23743 AN: 86248

European-Finnish (FIN) AF: 0.352 AC: 18791 AN: 53410

Middle Eastern (MID) AF: 0.291 AC: 1677 AN: 5768

European-Non Finnish (NFE) AF: 0.299 AC: 332790 AN: 1111768

Other (OTH) AF: 0.288 AC: 17373 AN: 60392

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

African (AFR) AF: 0.184 AC: 7649 AN: 41484

American (AMR) AF: 0.229 AC: 3493 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3466

East Asian (EAS) AF: 0.361 AC: 1866 AN: 5162

South Asian (SAS) AF: 0.284 AC: 1370 AN: 4826

European-Finnish (FIN) AF: 0.348 AC: 3671 AN: 10542

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.312 AC: 21199 AN: 67976

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.289 Hom.: 21975

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 v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.016	D
Sift4G	Benign	0.13	T
Polyphen		0.36	B
Vest4		0.48
MPC		0.53
ClinPred		0.048	T
GERP RS		4.7
Varity_R		0.65
gMVP		0.74
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

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