1-2399503-T-A

Position:

• chr1-2399503-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007033.5(RER1):​c.275T>A​(p.Met92Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M92V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RER1 NM_007033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31897235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RER1	NM_007033.5	c.275T>A	p.Met92Lys	missense_variant	4/7	ENST00000605895.6	NP_008964.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RER1	ENST00000605895.6	c.275T>A	p.Met92Lys	missense_variant	4/7	1	NM_007033.5	ENSP00000475168.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Sep 27, 2021

The c.275T>A (p.M92K) alteration is located in exon 4 (coding exon 3) of the RER1 gene. This alteration results from a T to A substitution at nucleotide position 275, causing the methionine (M) at amino acid position 92 to be replaced by a lysine (K). 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	Uncertain	0.54
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.13	T;.;T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;.;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.18	.;N;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.77	.;T;T;T;.
Sift4G	Benign	0.88	T;T;T;T;T
Polyphen		0.0020	B;.;B;.;B
Vest4		0.61
MutPred		0.47		Gain of ubiquitination at M92 (P = 0.0022);Gain of ubiquitination at M92 (P = 0.0022);Gain of ubiquitination at M92 (P = 0.0022);Gain of ubiquitination at M92 (P = 0.0022);Gain of ubiquitination at M92 (P = 0.0022);
MVP		0.14
MPC		1.4
ClinPred		0.72	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-2330942;