rs74315505

Variant names:

• chr22-29681443-G-A
• NM_000268.4:c.1579G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-29681443-G-A
• chr22-29681443-G-T

Variant summary

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

The NM_000268.4(NF2):​c.1579G>A​(p.Glu527Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95

Genes affected

NF2 (HGNC:7773): (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that link cytoskeletal components with proteins in the cell membrane. The encoded protein is involved in regulation of contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling. The encoded protein has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics, and proteins involved in regulating ion transport. Disruption of this protein's function has been implicated in tumorigenesis and metastasis. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4	c.1579G>A	p.Glu527Lys	missense_variant	Exon 15 of 16	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10	c.1579G>A	p.Glu527Lys	missense_variant	Exon 15 of 16	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E527K variant (also known as c.1579G>A), located in coding exon 15 of the NF2 gene, results from a G to A substitution at nucleotide position 1579. The glutamic acid at codon 527 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;.;.;D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.;M;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;D;D;N;D;D;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.030	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.42	T;T;T;T;T;T;T;T;T
Polyphen		0.79	P;P;P;P;D;D;P;D;P
Vest4		0.84
MutPred		0.49		Loss of ubiquitination at K525 (P = 0.011);.;.;Loss of ubiquitination at K525 (P = 0.011);.;.;Loss of ubiquitination at K525 (P = 0.011);.;Loss of ubiquitination at K525 (P = 0.011);
MVP		0.84
MPC		1.6
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.60
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30077432;