dbSNP rs12004: KDELR3:p.Val199Gly (chr22-38481456-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

Publications

49 publications found

Variant links:

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]

KDELR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDELR3	NM_006855.4 link	c.596T>G	p.Val199Gly	missense_variant	Exon 4 of 5	ENST00000216014.9	NP_006846.1	O43731-1A0A024R1R0
KDELR3	NM_016657.3 link	c.596T>G	p.Val199Gly	missense_variant	Exon 4 of 4		NP_057839.1	O43731-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDELR3	ENST00000216014.9 link	c.596T>G	p.Val199Gly	missense_variant	Exon 4 of 5	1	NM_006855.4	ENSP00000216014.4	O43731-1
KDELR3	ENST00000409006.3 link	c.596T>G	p.Val199Gly	missense_variant	Exon 4 of 4	1		ENSP00000386918.3	O43731-2
KDELR3	ENST00000471268.1 link	n.535T>G		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41282

AN:

151926

Hom.:

5903

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.296

AC XY:

215270

AN XY:

727098

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

16239

32477

48716

64954

81193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10870

21740

32610

43480

54350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.272

AC:

41316

AN:

152044

Hom.:

5909

Cov.:

AF XY:

0.273

AC XY:

20313

AN XY:

74306

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.312

AC:

21199

AN:

67976

Other (OTH)

AF:

0.273

AC:

575

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1503

3006

4509

6012

7515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

8.0

PrimateAI

Uncertain

0.52

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

GERP RS

4.7

Varity_R

0.65

gMVP

0.74

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over