21-32467842-C-G

Variant names:

• chr21-32467842-C-G
• rs200288953
• NM_058187.5:c.628C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_058187.5(EVA1C):​c.628C>G​(p.Pro210Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,607,910 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. P210T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (4 hom.)
• Consequence: EVA1C NM_058187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34
• Publications: 2 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038518548).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVA1C	NM_058187.5	c.628C>G	p.Pro210Ala	missense_variant	Exon 4 of 8	ENST00000300255.7	NP_478067.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVA1C	ENST00000300255.7	c.628C>G	p.Pro210Ala	missense_variant	Exon 4 of 8	1	NM_058187.5	ENSP00000300255.2

Frequencies

GnomAD3 genomes AF: 0.0000725 AC: 11 AN: 151822 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000361 AC: 88 AN: 244102 AF XY: 0.000378

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000921

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000564

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1455970 Hom.: 4 Cov.: 32 AF XY: 0.000214 AC XY: 155 AN XY: 724330

African (AFR) AF: 0.0000907 AC: 3 AN: 33084

American (AMR) AF: 0.000780 AC: 34 AN: 43596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39250

South Asian (SAS) AF: 0.00145 AC: 124 AN: 85248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53336

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5740

European-Non Finnish (NFE) AF: 0.0000622 AC: 69 AN: 1109698

Other (OTH) AF: 0.000116 AC: 7 AN: 60108

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151940 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74280

African (AFR) AF: 0.0000483 AC: 2 AN: 41386

American (AMR) AF: 0.000394 AC: 6 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628C>G (p.P210A) alteration is located in exon 4 (coding exon 4) of the EVA1C gene. This alteration results from a C to G substitution at nucleotide position 628, causing the proline (P) at amino acid position 210 to be replaced by an alanine (A). 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	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.0093	T;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L;.
PhyloP100		5.3
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.062	T;D;T;T
Polyphen		0.96	D;P;.;.
Vest4		0.39
MVP		0.36
MPC		0.73
ClinPred		0.073	T
GERP RS		5.6
Varity_R		0.072
gMVP		0.55
Mutation Taster		=61/39	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: rs200288953; hg19: chr21-33840150;