1-2402279-C-G

Position:

• chr1-2402279-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007033.5(RER1):​c.438C>G​(p.Phe146Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RER1 NM_007033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

RER1 (HGNC:30309): (retention in endoplasmic reticulum sorting receptor 1) The protein encoded by this gene is a multi-pass membrane protein that is localized to the golgi apparatus. It is involved in the retention of endoplasmic reticulum (ER) membrane proteins in the ER and retrieval of ER membrane proteins from the early Golgi compartment to facilitate gamma-secretase complex assembly. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RER1	NM_007033.5	c.438C>G	p.Phe146Leu	missense_variant	6/7	ENST00000605895.6	NP_008964.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RER1	ENST00000605895.6	c.438C>G	p.Phe146Leu	missense_variant	6/7	1	NM_007033.5	ENSP00000475168	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 22, 2023

The c.438C>G (p.F146L) alteration is located in exon 6 (coding exon 5) of the RER1 gene. This alteration results from a C to G substitution at nucleotide position 438, causing the phenylalanine (F) at amino acid position 146 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.82	D;.;T;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.7	H;.;.;H
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	.;D;D;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.80		Loss of catalytic residue at P144 (P = 0.181);Loss of catalytic residue at P144 (P = 0.181);Loss of catalytic residue at P144 (P = 0.181);Loss of catalytic residue at P144 (P = 0.181);
MVP		0.54
MPC		2.1
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.99

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: rs1344215226; hg19: chr1-2333718;