2-75493337-G-A

Variant names:

• chr2-75493337-G-A
• NM_001135032.2:c.358C>T

Variant summary

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

The NM_001135032.2(EVA1A):​c.358C>T​(p.Arg120Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R120S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EVA1A NM_001135032.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

Genes affected

EVA1A (HGNC:25816): (eva-1 homolog A, regulator of programmed cell death) Predicted to be involved in apoptotic process and autophagy. Located in intracellular membrane-bounded organelle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
EVA1A	NM_001135032.2	c.358C>T	p.Arg120Cys	missense_variant	Exon 4 of 4	ENST00000393913.8	NP_001128504.1
EVA1A	NM_001369524.1	c.358C>T	p.Arg120Cys	missense_variant	Exon 6 of 6		NP_001356453.1
EVA1A	NM_001369525.1	c.358C>T	p.Arg120Cys	missense_variant	Exon 5 of 5		NP_001356454.1
EVA1A	NM_032181.3	c.358C>T	p.Arg120Cys	missense_variant	Exon 4 of 4		NP_115557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVA1A	ENST00000393913.8	c.358C>T	p.Arg120Cys	missense_variant	Exon 4 of 4	1	NM_001135032.2	ENSP00000377490.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461828 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358C>T (p.R120C) alteration is located in exon 4 (coding exon 2) of the EVA1A gene. This alteration results from a C to T substitution at nucleotide position 358, causing the arginine (R) at amino acid position 120 to be replaced by a cysteine (C). 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	0.80
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T;T;T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.99	.;D;.;D;.;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.3	M;M;M;.;M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.68
MutPred		0.32		Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);.;Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);
MVP		0.76
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-75720463; COSMIC: COSV52062676; COSMIC: COSV52062676;