chr17-31318638-A-C

Position:

• chr17-31318638-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014210.4(EVI2A):​c.376T>G​(p.Cys126Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 6.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVI2A	NM_014210.4	c.376T>G	p.Cys126Gly	missense_variant	2/2	ENST00000462804.3	NP_055025.2
NF1	NM_001042492.3	c.4836-7182A>C		intron_variant		ENST00000358273.9	NP_001035957.1
EVI2A	NM_001003927.3	c.445T>G	p.Cys149Gly	missense_variant	3/3		NP_001003927.1
NF1	NM_000267.3	c.4773-7182A>C		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVI2A	ENST00000462804.3	c.376T>G	p.Cys126Gly	missense_variant	2/2	1	NM_014210.4	ENSP00000420557.3
ENSG00000265118	ENST00000578584.5	c.148T>G	p.Cys50Gly	missense_variant	1/3	2		ENSP00000463981.2
NF1	ENST00000358273.9	c.4836-7182A>C		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 01, 2024

The c.445T>G (p.C149G) alteration is located in exon 3 (coding exon 2) of the EVI2A gene. This alteration results from a T to G substitution at nucleotide position 445, causing the cysteine (C) at amino acid position 149 to be replaced by a glycine (G). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	.;T;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.60	T;.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.7	.;M;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-9.0	.;D;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.89
MutPred		0.87		.;Gain of disorder (P = 0.0019);.;Gain of disorder (P = 0.0019);
MVP		0.49
MPC		0.23
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29645656;