17-31304952-T-C

Variant summary

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

The NM_006495.4(EVI2B):c.658A>G(p.Ile220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: EVI2B NM_006495.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.573

Genes affected

EVI2B (HGNC:3500): (ecotropic viral integration site 2B) Involved in positive regulation of granulocyte differentiation. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057886273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVI2B	NM_006495.4	c.658A>G	p.Ile220Val	missense_variant	2/2	ENST00000330927.5
NF1	NM_001042492.3	c.4836-20868T>C		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.4773-20868T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVI2B	ENST00000330927.5	c.658A>G	p.Ile220Val	missense_variant	2/2	1	NM_006495.4	P1
NF1	ENST00000358273.9	c.4836-20868T>C		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251130 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 191 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000654 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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 08, 2023

The c.658A>G (p.I220V) alteration is located in exon 2 (coding exon 1) of the EVI2B gene. This alteration results from a A to G substitution at nucleotide position 658, causing the isoleucine (I) at amino acid position 220 to be replaced by a valine (V). 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	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	7.3
Dann	Benign	0.83
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.048	N
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.82	N;.
REVEL	Benign	0.010
Sift	Benign	0.058	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.21	B;B
Vest4		0.11
MVP		0.50
MPC		0.060
ClinPred		0.027	T
GERP RS		-0.052
Varity_R		0.050
gMVP		0.12

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: rs148276474; hg19: chr17-29631970;