2-75493571-C-A

Variant names:

• chr2-75493571-C-A
• rs569896369
• NM_001135032.2:c.124G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001135032.2(EVA1A):​c.124G>T​(p.Val42Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V42M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: EVA1A NM_001135032.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 2 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135032.2. 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
	EVA1A	NM_001135032.2	MANE Select	c.124G>T	p.Val42Leu	missense	Exon 4 of 4	NP_001128504.1	Q9H8M9
	EVA1A	NM_001369524.1		c.124G>T	p.Val42Leu	missense	Exon 6 of 6	NP_001356453.1	Q9H8M9
	EVA1A	NM_001369525.1		c.124G>T	p.Val42Leu	missense	Exon 5 of 5	NP_001356454.1	Q9H8M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVA1A	ENST00000393913.8	TSL:1 MANE Select	c.124G>T	p.Val42Leu	missense	Exon 4 of 4	ENSP00000377490.3	Q9H8M9
	EVA1A	ENST00000910300.1		c.181G>T	p.Val61Leu	missense	Exon 4 of 4	ENSP00000580359.1
	EVA1A	ENST00000910305.1		c.181G>T	p.Val61Leu	missense	Exon 3 of 3	ENSP00000580364.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248328 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460420 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726392

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111234

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000227 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		3.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.76		Loss of sheet (P = 0.1907)
MVP		0.86
MPC		0.97
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.61
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs569896369; hg19: chr2-75720697;