22-29604105-A-T

Position:

• chr22-29604105-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000268.4(NF2):​c.107A>T​(p.Asn36Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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]

NF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain FERM (size 289) in uniprot entity MERL_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_000268.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32670072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF2	NM_000268.4	c.107A>T	p.Asn36Ile	missense_variant	1/16	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10	c.107A>T	p.Asn36Ile	missense_variant	1/16	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2019

The p.N36I variant (also known as c.107A>T), located in coding exon 1 of the NF2 gene, results from an A to T substitution at nucleotide position 107. The asparagine at codon 36 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.13
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;.;.;.;.;.;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;.;D;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L;L;L;L;L;L;L;L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;N;D;D;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.031	D;T;T;T;T;D;D;T;D;T
Sift4G	Benign	0.19	T;D;D;T;D;D;D;D;D;D
Polyphen		0.36	B;P;.;B;B;B;B;B;B;B
Vest4		0.48
MutPred		0.50		Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);Loss of catalytic residue at N36 (P = 0.0269);
MVP		0.85
MPC		0.88
ClinPred		0.87	D
GERP RS		0.75
Varity_R		0.45
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372279458; hg19: chr22-30000094;