rs199474777

chr17-31227260-G-Achr17-31227260-G-Cchr17-31227260-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001042492.3(NF1):c.2294G>A(p.Arg765His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R765C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6 O:1
• Conservation: PhyloP100: 9.48

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.18585953).
• BP6: Variant 17-31227260-G-A is Benign according to our data. Variant chr17-31227260-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68313.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=5, Benign=1, Uncertain_significance=4}.
• BS2: High AC in GnomAdExome at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2294G>A	p.Arg765His	missense_variant	19/58	ENST00000358273.9
NF1	NM_000267.3	c.2294G>A	p.Arg765His	missense_variant	19/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2294G>A	p.Arg765His	missense_variant	19/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.0000798 AC: 20 AN: 250754 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461410 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Neurofibromatosis 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. -

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NF1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	This variant is associated with the following publications: (PMID: 9195229, 10336779, 24448499) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2015	The p.R765H variant (also known as c.2294G>A), located in coding exon 19 of the NF1 gene, results from a G to A substitution at nucleotide position 2294.This variant was reported in one NF1 patient but not in affected relatives(Abernathy CR, et al. Hum.Mutat. 1997 ; 9(6):548-54). The arginine at codon 765 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs199474777.To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than55000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence for this variant is limited at this time, the clinical significance ofp.R765Hremains unclear. -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

research

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Nov 10, 2018

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 10, 2022

Variant summary: NF1 c.2294G>A (p.Arg765His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250754 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2294G>A has been reported in the literature poorly segregating in individuals affected with Neurofibromatosis Type 1 within a family (e.g. Abernathy_1997, Krkljus_1998), while it was also reported in individuals unaffected with NF1 (Zhu_2019, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

This alteration is classified as benign based on a combination of the following: 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.94	P;D;.
Vest4		0.83
MVP		0.77
MPC		1.4
ClinPred		0.36	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199474777; hg19: chr17-29554278; COSMIC: COSV62201563; COSMIC: COSV62201563;