chr22-29603999-A-G

Position:

• chr22-29603999-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000268.4(NF2):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000014 in 1,427,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF2 NM_000268.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 6.20

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.1A>G	p.Met1?	start_lost	1/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.1A>G	p.Met1?	start_lost	1/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1427106 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 706822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 2 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This variant results in the loss of the translation initiator methionine at codon 1 of the NF2 protein. The NF2 gene encodes for a methionine codon 9 before known functional domains (PMID: 25893302) and a second methionine at codon 29. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2022	This sequence change affects the initiator methionine of the NF2 mRNA. The next in-frame methionine is located at codon 9. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 956856). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2019

Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31130284) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.34	.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	0.75	D;D;D;D;D;N;N;N
PROVEAN	Benign	-0.49	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.043	B;P;.;P;P;B;B;P;P;P
Vest4		0.89
MutPred		0.94		Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);Loss of MoRF binding (P = 0.1375);
MVP		0.96
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.76

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: rs1319282473; hg19: chr22-29999988;