17-31319014-G-T

Variant names:

• chr17-31319014-G-T
• rs1129506
• NM_014210.4:c.-1C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001003927.3(EVI2A):​c.69C>A​(p.Ser23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EVI2A NM_001003927.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580
• Publications: 0 publications found

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]

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000265118 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09094399).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003927.3. 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
	EVI2A	NM_014210.4	MANE Select	c.-1C>A		5_prime_UTR	Exon 2 of 2	NP_055025.2
	NF1	NM_001042492.3	MANE Select	c.4836-6806G>T		intron	N/A	NP_001035957.1
	EVI2A	NM_001003927.3		c.69C>A	p.Ser23Arg	missense	Exon 3 of 3	NP_001003927.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVI2A	ENST00000462804.3	TSL:1 MANE Select	c.-1C>A		5_prime_UTR	Exon 2 of 2	ENSP00000420557.3
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.4836-6806G>T		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.4773-6806G>T		intron	N/A	ENSP00000348498.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439174 Hom.: 0 Cov.: 39 AF XY: 0.00000140 AC XY: 1 AN XY: 715178

African (AFR) AF: 0.00 AC: 0 AN: 32454

American (AMR) AF: 0.00 AC: 0 AN: 40698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 83820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104510

Other (OTH) AF: 0.0000168 AC: 1 AN: 59560

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.5
DANN	Benign	0.80
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.058
PROVEAN	Benign	0.020	N
REVEL	Benign	0.014
Sift	Benign	0.068	T
Polyphen		0.044	B
Vest4		0.19
MutPred		0.26		Gain of catalytic residue at S23 (P = 0.012)
MVP		0.17
MPC		0.032
ClinPred		0.19	T
GERP RS		1.4
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.22

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: rs1129506; hg19: chr17-29646032;