17-31318345-A-T

Position:

• chr17-31318345-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014210.4(EVI2A):​c.669T>A​(p.Asp223Glu) 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVI2A NM_014210.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.163

Genes affected

EVI2A (HGNC:3499): (ecotropic viral integration site 2A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000265118 (HGNC:):

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073649794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVI2A	NM_014210.4	c.669T>A	p.Asp223Glu	missense_variant	2/2	ENST00000462804.3	NP_055025.2
NF1	NM_001042492.3	c.4836-7475A>T		intron_variant		ENST00000358273.9	NP_001035957.1
EVI2A	NM_001003927.3	c.738T>A	p.Asp246Glu	missense_variant	3/3		NP_001003927.1
NF1	NM_000267.3	c.4773-7475A>T		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVI2A	ENST00000462804.3	c.669T>A	p.Asp223Glu	missense_variant	2/2	1	NM_014210.4	ENSP00000420557.3
ENSG00000265118	ENST00000578584.5	c.441T>A	p.Asp147Glu	missense_variant	1/3	2		ENSP00000463981.2
NF1	ENST00000358273.9	c.4836-7475A>T		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246930 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133384

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Aug 14, 2024

The c.738T>A (p.D246E) alteration is located in exon 3 (coding exon 2) of the EVI2A gene. This alteration results from a T to A substitution at nucleotide position 738, causing the aspartic acid (D) at amino acid position 246 to be replaced by a glutamic acid (E). 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	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0080	.;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.47	T;.;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.074	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	.;M;.;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	.;N;N;.
REVEL	Benign	0.089
Sift	Benign	0.49	.;T;T;.
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.98, 0.98	.;D;D;D
Vest4		0.14
MutPred		0.37		.;Loss of loop (P = 0.0986);.;Loss of loop (P = 0.0986);
MVP		0.11
MPC		0.043
ClinPred		0.73	D
GERP RS		3.5
Varity_R		0.049
gMVP		0.015

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs756337378; hg19: chr17-29645363;