chr22-38479627-A-G

Position:

• chr22-38479627-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006855.4(KDELR3):​c.227A>G​(p.Tyr76Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,613,984 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: KDELR3 NM_006855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18365392).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDELR3	NM_006855.4	c.227A>G	p.Tyr76Cys	missense_variant	3/5	ENST00000216014.9	NP_006846.1
KDELR3	NM_016657.3	c.227A>G	p.Tyr76Cys	missense_variant	3/4		NP_057839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDELR3	ENST00000216014.9	c.227A>G	p.Tyr76Cys	missense_variant	3/5	1	NM_006855.4	ENSP00000216014.4
KDELR3	ENST00000409006.3	c.227A>G	p.Tyr76Cys	missense_variant	3/4	1		ENSP00000386918.3
KDELR3	ENST00000471268.1	n.166A>G		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152206 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00143 AC: 359 AN: 251474 Hom.: 0 AF XY: 0.00152 AC XY: 206 AN XY: 135916

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00238 AC: 3473 AN: 1461660 Hom.: 11 Cov.: 32 AF XY: 0.00234 AC XY: 1704 AN XY: 727150

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152324 Hom.: 2 Cov.: 31 AF XY: 0.00144 AC XY: 107 AN XY: 74482

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00246 Hom.: 2

Bravo AF: 0.00181

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00130 AC: 158

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.227A>G (p.Y76C) alteration is located in exon 3 (coding exon 3) of the KDELR3 gene. This alteration results from a A to G substitution at nucleotide position 227, causing the tyrosine (Y) at amino acid position 76 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.63
MPC		0.64
ClinPred		0.11	T
GERP RS		3.6
Varity_R		0.74
gMVP		0.90

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: rs138428820; hg19: chr22-38875632; COSMIC: COSV99318473; COSMIC: COSV99318473;