1-92513963-C-T

Variant names:

• chr1-92513963-C-T
• rs1283685554
• NM_001350197.2:c.2174G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001350197.2(EVI5):​c.2174G>A​(p.Cys725Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000324 in 1,543,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: EVI5 NM_001350197.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350197.2. 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
	EVI5	NM_001350197.2	MANE Select	c.2174G>A	p.Cys725Tyr	missense	Exon 20 of 20	NP_001337126.1	A0A804HIC4
	EVI5	NM_001308248.2		c.2159G>A	p.Cys720Tyr	missense	Exon 19 of 19	NP_001295177.1	O60447-2
	EVI5	NM_001377210.1		c.2150G>A	p.Cys717Tyr	missense	Exon 19 of 19	NP_001364139.1	A0A9L9PXL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVI5	ENST00000684568.2	MANE Select	c.2174G>A	p.Cys725Tyr	missense	Exon 20 of 20	ENSP00000506999.1	A0A804HIC4
	EVI5	ENST00000540033.3	TSL:1	c.2159G>A	p.Cys720Tyr	missense	Exon 19 of 19	ENSP00000440826.2	O60447-2
	EVI5	ENST00000370331.5	TSL:1	c.2126G>A	p.Cys709Tyr	missense	Exon 18 of 18	ENSP00000359356.1	O60447-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000146 AC: 3 AN: 205290 AF XY: 0.0000182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000177

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1391690 Hom.: 0 Cov.: 30 AF XY: 0.00000438 AC XY: 3 AN XY: 684994

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31484

American (AMR) AF: 0.00 AC: 0 AN: 37050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22240

East Asian (EAS) AF: 0.0000777 AC: 3 AN: 38606

South Asian (SAS) AF: 0.00 AC: 0 AN: 74764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074062

Other (OTH) AF: 0.00 AC: 0 AN: 57120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0240912), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.20
Sift	Benign	0.15	T
Sift4G	Benign	0.55	T
Polyphen		0.99	D
Vest4		0.80
MutPred		0.17		Loss of catalytic residue at L721 (P = 0.0401)
MVP		0.60
MPC		0.55
ClinPred		0.60	D
GERP RS		5.9
Varity_R		0.37
gMVP		0.53
Mutation Taster		=45/55	disease causing

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: rs1283685554; hg19: chr1-92979520;