1-92513741-C-T

Position:

• chr1-92513741-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001350197.2(EVI5):​c.2396G>A​(p.Ser799Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: EVI5 NM_001350197.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.586

Genes affected

EVI5 (HGNC:3501): (ecotropic viral integration site 5) Enables GTPase activator activity and small GTPase binding activity. Involved in positive regulation of GTPase activity and retrograde transport, endosome to Golgi. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060182333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVI5	NM_001350197.2	c.2396G>A	p.Ser799Asn	missense_variant	20/20	ENST00000684568.2	NP_001337126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVI5	ENST00000684568.2	c.2396G>A	p.Ser799Asn	missense_variant	20/20		NM_001350197.2	ENSP00000506999	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.2348G>A (p.S783N) alteration is located in exon 18 (coding exon 18) of the EVI5 gene. This alteration results from a G to A substitution at nucleotide position 2348, causing the serine (S) at amino acid position 783 to be replaced by an asparagine (N). 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	0.066
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0050	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.10
Sift	Benign	0.083	T;.
Sift4G	Benign	0.71	T;T
Polyphen		0.0	B;.
Vest4		0.067
MutPred		0.037		.;Loss of phosphorylation at S794 (P = 0.0091);
MVP		0.32
MPC		0.14
ClinPred		0.083	T
GERP RS		4.0
Varity_R		0.064
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs1659409038; hg19: chr1-92979298; COSMIC: COSV100945124;