rs1556003698

Variant names:

• chr22-29681499-A-T
• rs1556003698
• NM_000268.4:c.1635A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1 PP3 BS1 BS2

The NM_000268.4(NF2):​c.1635A>T​(p.Glu545Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,882 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E545K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.02
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• NF2-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 27 uncertain in NM_000268.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000205 (30/1461882) while in subpopulation NFE AF = 0.000027 (30/1112006). AF 95% confidence interval is 0.0000191. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 30 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.1635A>T	p.Glu545Asp	missense	Exon 15 of 16	NP_000259.1	P35240-1
	NF2	NM_001407066.1		c.1635A>T	p.Glu545Asp	missense	Exon 15 of 17	NP_001393995.1	P35240-3
	NF2	NM_016418.5		c.1635A>T	p.Glu545Asp	missense	Exon 15 of 17	NP_057502.2	P35240-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.1635A>T	p.Glu545Asp	missense	Exon 15 of 16	ENSP00000344666.5	P35240-1
	NF2	ENST00000397789.3	TSL:1	c.1635A>T	p.Glu545Asp	missense	Exon 15 of 17	ENSP00000380891.3	P35240-3
	NF2	ENST00000403999.7	TSL:1	c.1635A>T	p.Glu545Asp	missense	Exon 15 of 16	ENSP00000384797.3	P35240-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Neurofibromatosis, type 2 (3)
-	1	-	Familial meningioma (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.69
Sift	Benign	0.064	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.74		Gain of phosphorylation at T544 (P = 0.2079)
MVP		0.90
MPC		1.6
ClinPred		0.88	D
GERP RS		-0.20
Varity_R		0.28
gMVP		0.51
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1556003698; hg19: chr22-30077488;