chr2-53797585-C-G

Variant names:

• chr2-53797585-C-G
• rs751933066
• NM_015701.5:c.419C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_015701.5(ERLEC1):​c.419C>G​(p.Thr140Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T140I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERLEC1 NM_015701.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.32
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-53797585-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 830378.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 2-53797585-C-G is Pathogenic according to our data. Variant chr2-53797585-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 830377.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13825148). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015701.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLEC1	NM_015701.5	MANE Select	c.419C>G	p.Thr140Ser	missense	Exon 4 of 14	NP_056516.2
	ERLEC1	NM_001127397.3		c.419C>G	p.Thr140Ser	missense	Exon 4 of 13	NP_001120869.1	Q96DZ1-3
	ERLEC1	NM_001127398.3		c.419C>G	p.Thr140Ser	missense	Exon 4 of 13	NP_001120870.1	Q96DZ1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLEC1	ENST00000185150.9	TSL:1 MANE Select	c.419C>G	p.Thr140Ser	missense	Exon 4 of 14	ENSP00000185150.4	Q96DZ1-1
	ERLEC1	ENST00000378239.5	TSL:1	c.419C>G	p.Thr140Ser	missense	Exon 4 of 13	ENSP00000367485.5	Q96DZ1-2
	ERLEC1	ENST00000952242.1		c.419C>G	p.Thr140Ser	missense	Exon 4 of 14	ENSP00000622301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249370 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459386 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725866

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111044

Other (OTH) AF: 0.00 AC: 0 AN: 60314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mandibular prognathia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.064
Sift	Benign	0.53	T
Sift4G	Benign	0.56	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.29		Gain of sheet (P = 0.0085)
MVP		0.30
MPC		0.20
ClinPred		0.72	D
GERP RS		4.6
Varity_R		0.092
gMVP		0.28
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs751933066; hg19: chr2-54024722;