22-29678289-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000268.4(NF2):c.1540A>G(p.Met514Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M514L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 7.32

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 Benign. Variant got -9 ACMG points.

• PM1: In a helix (size 34) in uniprot entity MERL_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000268.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.2284613).
• BP6: Variant 22-29678289-A-G is Benign according to our data. Variant chr22-29678289-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201125.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000919 (14/152322) while in subpopulation AMR AF= 0.000392 (6/15302). AF 95% confidence interval is 0.00017. There are 1 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.1540A>G	p.Met514Val	missense_variant	14/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.1540A>G	p.Met514Val	missense_variant	14/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251494 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 2 Uncertain:6 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 514 of the NF2 protein (p.Met514Val). This variant is present in population databases (rs201527155, gnomAD 0.02%). This missense change has been observed in individual(s) with bilateral vestibular schwannomas and/or breast cancer (PMID: 16983642, 35264596). ClinVar contains an entry for this variant (Variation ID: 201125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NF2 function (PMID: 26045165). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 chromosomes 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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 chromosomes 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	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	The NF2 c.1540A>G; p.Met514Val variant (rs201527155) is reported in the literature in an individual with bilateral vestibular schwannoma, but was not determined to be causative (Ahronowitz 2007). The variant is reported in the ClinVar database (Variation ID: 201125) and is reported in the general population with an overall allele frequency of 0.0099% (28/282,872 alleles) in the Genome Aggregation Database. The methionine at codon 514 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of the p.Met514Val variant is uncertain at this time. Gene Statement: References: Ahronowitz I et al. Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007 Jan;28(1):1-12. PMID: 16983642. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2022	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -

NF2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The NF2 c.1540A>G variant is predicted to result in the amino acid substitution p.Met514Val. This variant was reported in an individual with bilateral vestibular schwannomas; however, pathogenicity was not established (Ahronowitz et al 2007. PubMed ID: 16983642). This variant was also reported as a variant of uncertain significance in a large study of Brazilian breast cancer patients (Supp Table 3 in Guindalini RSC et al 2022. PubMed ID: 35264596). This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD, which is likely too common for an autosomal dominant disorder. This variant is reported in ClinVar with conflicting interpretations of uncertain and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/201125/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial meningioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.
Eigen	Benign	0.037
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;.;.;D;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.7	L;.;.;L;.;.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.27	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B;B;B;B;B
Vest4		0.59
MVP		0.97
MPC		0.83
ClinPred		0.066	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.34
gMVP		0.55

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: rs201527155; hg19: chr22-30074278; COSMIC: COSV58519585;