2-53795936-G-A

Position:

• chr2-53795936-G-A

Variant summary

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

The NM_015701.5(ERLEC1):​c.271G>A​(p.Glu91Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,433,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ERLEC1 NM_015701.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

Genes affected

ERLEC1 (HGNC:25222): (endoplasmic reticulum lectin 1) This gene encodes a resident endoplasmic reticulum (ER) protein that functions in N-glycan recognition. This protein is thought to be involved in ER-associated degradation via its interaction with the membrane-associated ubiquitin ligase complex. It also functions as a regulator of multiple cellular stress-response pathways in a manner that promotes metastatic cell survival. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 21. [provided by RefSeq, Aug 2011]

GPR75-ASB3 (HGNC:40043): (GPR75-ASB3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring GPR75 (G protein-coupled receptor 75) and ASB3 (ankyrin repeat and SOCS box containing 3) on chromosome 2. The transcript includes exons from both GPR75 and ASB3 and translation initiates in the 5' non-coding exon of GPR75. The resulting protein has a novel N-terminus but is otherwise identical to that encoded by ASB3.[provided by RefSeq, Feb 2011]

ASB3 (HGNC:16013): (ankyrin repeat and SOCS box containing 3) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jan 2011]

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
ERLEC1	NM_015701.5	c.271G>A	p.Glu91Lys	missense_variant	3/14	ENST00000185150.9	NP_056516.2
ERLEC1	NM_001127397.3	c.271G>A	p.Glu91Lys	missense_variant	3/13		NP_001120869.1
ERLEC1	NM_001127398.3	c.271G>A	p.Glu91Lys	missense_variant	3/13		NP_001120870.1
GPR75-ASB3	NM_001164165.2	c.102-30351C>T		intron_variant			NP_001157637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLEC1	ENST00000185150.9	c.271G>A	p.Glu91Lys	missense_variant	3/14	1	NM_015701.5	ENSP00000185150.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000132 AC: 3 AN: 227456 Hom.: 0 AF XY: 0.0000162 AC XY: 2 AN XY: 123450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433232 Hom.: 0 Cov.: 28 AF XY: 0.00000280 AC XY: 2 AN XY: 713336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000800

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Jul 31, 2024

The c.271G>A (p.E91K) alteration is located in exon 3 (coding exon 3) of the ERLEC1 gene. This alteration results from a G to A substitution at nucleotide position 271, causing the glutamic acid (E) at amino acid position 91 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	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;T;.
Eigen	Benign	0.034
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.32, 0.046	.;B;B
Vest4		0.57
MutPred		0.38		Gain of ubiquitination at E91 (P = 0.0109);Gain of ubiquitination at E91 (P = 0.0109);Gain of ubiquitination at E91 (P = 0.0109);
MVP		0.31
MPC		0.24
ClinPred		0.55	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs755460433; hg19: chr2-54023073;