14-52658007-G-T

Variant names:

• chr14-52658007-G-T
• rs757739519
• NM_014584.3:c.718C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014584.3(ERO1A):​c.718C>A​(p.Leu240Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L240F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ERO1A NM_014584.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

Genes affected

ERO1A (HGNC:13280): (endoplasmic reticulum oxidoreductase 1 alpha) Enables oxidoreductase activity. Involved in chaperone cofactor-dependent protein refolding. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014584.3. 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
	ERO1A	NM_014584.3	MANE Select	c.718C>A	p.Leu240Ile	missense splice_region	Exon 11 of 16	NP_055399.1	Q96HE7
	ERO1A	NM_001382464.1		c.757C>A	p.Leu253Ile	missense splice_region	Exon 12 of 17	NP_001369393.1
	ERO1A	NM_001382465.1		c.706C>A	p.Leu236Ile	missense splice_region	Exon 10 of 15	NP_001369394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERO1A	ENST00000395686.8	TSL:1 MANE Select	c.718C>A	p.Leu240Ile	missense splice_region	Exon 11 of 16	ENSP00000379042.3	Q96HE7
	ERO1A	ENST00000629528.2	TSL:5	c.716C>A	p.Ser239Tyr	missense	Exon 9 of 9	ENSP00000487101.1	G3V3E6
	ERO1A	ENST00000964628.1		c.757C>A	p.Leu253Ile	missense splice_region	Exon 12 of 17	ENSP00000634687.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450680 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721918

African (AFR) AF: 0.00 AC: 0 AN: 33034

American (AMR) AF: 0.00 AC: 0 AN: 43686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 84348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104932

Other (OTH) AF: 0.00 AC: 0 AN: 60032

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Benign	0.074	T
Polyphen		0.87	P
Vest4		0.39
MutPred		0.50		Gain of methylation at K244 (P = 0.0666)
MVP		0.39
MPC		0.56
ClinPred		0.94	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.21
Mutation Taster		=85/15	polymorphism

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: rs757739519; hg19: chr14-53124725; COSMIC: COSV67471112;