chr22-29673378-G-A

Position:

chr22-29673378-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_000268.4(NF2):c.1232G>A(p.Arg411His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,898 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R411C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 9.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000178 (26/1458648) while in subpopulation AMR AF= 0.000113 (5/44234). AF 95% confidence interval is 0.000044. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4 linkuse as main transcript	c.1232G>A	p.Arg411His	missense_variant	12/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10 linkuse as main transcript	c.1232G>A	p.Arg411His	missense_variant	12/16	1	NM_000268.4	P1	P35240-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000287

AC:

AN:

243548

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1458648

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 411 of the NF2 protein (p.Arg411His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 527695). 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%. 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	Genome-Nilou Lab	Nov 07, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg411His variant in NF2 has not been previously reported in individuals with Neurofibromatosis but has been identified in 0.01181% (4/33872) of Latino chromosomes, 0.003403% (1/29382) of South Asian chromosomes, and 0.0009079% (1/110142) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201214090). This variant has also been reported as a VUS in ClinVar (Variation ID: 527695). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg411Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 567682). In summary, while the clinical significance of the p.Arg411His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015). -

Neurofibromatosis, type 2;C3551915:Familial meningioma;C4048809:Schwannomatosis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16324214, 17134719, 22482125, 27930734) -

Familial meningioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 05, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;.;.;D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

3.0

M;.;.;M;.;.;M;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.037

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D;D;D;D

Vest4

0.69

MutPred

0.50

Loss of MoRF binding (P = 0.0064);.;.;Loss of MoRF binding (P = 0.0064);.;.;Loss of MoRF binding (P = 0.0064);.;Loss of MoRF binding (P = 0.0064);

MVP

0.88

MPC

1.8

ClinPred

0.88

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over