NM_006495.4:c.995C>T

Variant names:

• chr17-31304615-G-A
• rs762579703
• NM_006495.4:c.995C>T

Variant summary

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

The NM_006495.4(EVI2B):​c.995C>T​(p.Ser332Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S332Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EVI2B NM_006495.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006495.4. 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
	EVI2B	NM_006495.4	MANE Select	c.995C>T	p.Ser332Phe	missense	Exon 2 of 2	NP_006486.3
	NF1	NM_001042492.3	MANE Select	c.4836-21205G>A		intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.4773-21205G>A		intron	N/A	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVI2B	ENST00000330927.5	TSL:1 MANE Select	c.995C>T	p.Ser332Phe	missense	Exon 2 of 2	ENSP00000333779.4	P34910-1
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.4836-21205G>A		intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.4773-21205G>A		intron	N/A	ENSP00000348498.3	P21359-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.17
Sift	Uncertain	0.012	D
Sift4G	Benign	0.069	T
Polyphen		0.98	D
Vest4		0.17
MVP		0.74
MPC		0.25
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.18
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762579703; hg19: chr17-29631633;