chr19-7847869-G-A

Position:

• chr19-7847869-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001159944.3(EVI5L):​c.275G>A​(p.Arg92Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,442,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EVI5L NM_001159944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

Genes affected

EVI5L (HGNC:30464): (ecotropic viral integration site 5 like) Enables GTPase activator activity and small GTPase binding activity. Involved in negative regulation of cilium assembly and positive regulation of GTPase activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVI5L	NM_001159944.3	c.275G>A	p.Arg92Gln	missense_variant	3/20	ENST00000538904.7	NP_001153416.1
EVI5L	NM_145245.5	c.275G>A	p.Arg92Gln	missense_variant	3/19		NP_660288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVI5L	ENST00000538904.7	c.275G>A	p.Arg92Gln	missense_variant	3/20	1	NM_001159944.3	ENSP00000445905.1
EVI5L	ENST00000270530.8	c.275G>A	p.Arg92Gln	missense_variant	3/19	1		ENSP00000270530.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442226 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2 AN XY: 716080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

May 27, 2022

The c.275G>A (p.R92Q) alteration is located in exon 2 (coding exon 2) of the EVI5L gene. This alteration results from a G to A substitution at nucleotide position 275, causing the arginine (R) at amino acid position 92 to be replaced by a glutamine (Q). 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	0.21
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.092	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.69	P;.
Vest4		0.77
MutPred		0.32		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);
MVP		0.44
MPC		1.3
ClinPred		0.93	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.75

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: rs1979031421; hg19: chr19-7912755;