Genetic Variant EVA1C:p.Arg22Cys (chr21-32412917-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_058187.5(EVA1C):c.64C>T(p.Arg22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,523,818 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: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

EVA1C
NM_058187.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

Publications

0 publications found

Variant links:

Genes affected

EVA1C (HGNC:13239): (eva-1 homolog C) Enables heparin binding activity. Colocalizes with extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

EVA1C links:

CFAP298-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

CFAP298-TCP10L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12803766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVA1C	NM_058187.5 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 1 of 8	ENST00000300255.7	NP_478067.2	P58658-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVA1C	ENST00000300255.7 link	c.64C>T	p.Arg22Cys	missense_variant	Exon 1 of 8	1	NM_058187.5	ENSP00000300255.2		P58658-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000559

AC:

AN:

125334

AF XY:

0.0000722

show subpopulations

Gnomad AFR exome

AF:

0.000236

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:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

153

AN:

1371592

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

677130

show subpopulations

African (AFR)

AF:

0.000351

AC:

AN:

28530

American (AMR)

AF:

0.00

AC:

AN:

33228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24426

East Asian (EAS)

AF:

0.00

AC:

AN:

32270

South Asian (SAS)

AF:

0.00

AC:

AN:

76808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.000127

AC:

136

AN:

1069998

Other (OTH)

AF:

0.000123

AC:

AN:

56966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000173

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64C>T (p.R22C) alteration is located in exon 1 (coding exon 1) of the EVA1C gene. This alteration results from a C to T substitution at nucleotide position 64, causing the arginine (R) at amino acid position 22 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0083

T;T;.

Eigen

Benign

-0.059

Eigen_PC

Benign

0.063

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;L

PhyloP100

3.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.044

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.0080

B;B;.

Vest4

0.54

MVP

0.26

MPC

0.44

ClinPred

0.097

GERP RS

4.2

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.19

gMVP

0.44

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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21-32412917-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over