22-38479617-G-C

Position:

• chr22-38479617-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006855.4(KDELR3):​c.217G>C​(p.Val73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
• Consequence: KDELR3 NM_006855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDELR3	NM_006855.4	c.217G>C	p.Val73Leu	missense_variant	3/5	ENST00000216014.9	NP_006846.1
KDELR3	NM_016657.3	c.217G>C	p.Val73Leu	missense_variant	3/4		NP_057839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDELR3	ENST00000216014.9	c.217G>C	p.Val73Leu	missense_variant	3/5	1	NM_006855.4	ENSP00000216014.4
KDELR3	ENST00000409006.3	c.217G>C	p.Val73Leu	missense_variant	3/4	1		ENSP00000386918.3
KDELR3	ENST00000471268.1	n.156G>C		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Nov 10, 2024

The c.217G>C (p.V73L) alteration is located in exon 3 (coding exon 3) of the KDELR3 gene. This alteration results from a G to C substitution at nucleotide position 217, causing the valine (V) at amino acid position 73 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.033
Sift	Benign	0.44	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;B
Vest4		0.36
MutPred		0.45		Loss of catalytic residue at V73 (P = 0.0452);Loss of catalytic residue at V73 (P = 0.0452);
MVP		0.28
MPC		0.13
ClinPred		0.34	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1348413190; hg19: chr22-38875622;