rs201712827

chr17-31336659-A-Gchr17-31336659-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001042492.3(NF1):c.6172A>G(p.Ile2058Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,330 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).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6 O:1
• Conservation: PhyloP100: 8.73

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.030422658).
• BP6: Variant 17-31336659-A-G is Benign according to our data. Variant chr17-31336659-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134887.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, not_provided=1, Likely_benign=5, Benign=1}.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6172A>G	p.Ile2058Val	missense_variant	42/58	ENST00000358273.9
NF1	NM_000267.3	c.6109A>G	p.Ile2037Val	missense_variant	41/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6172A>G	p.Ile2058Val	missense_variant	42/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000839 AC: 21 AN: 250150 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000193 AC: 282 AN: 1461322 Hom.: 0 Cov.: 34 AF XY: 0.000187 AC XY: 136 AN XY: 726918

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74212

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 28, 2022	_x000D_ Criteria applied: PP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 20, 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. -

not specified Uncertain:2 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 19, 2017	The p.Ile2058Val variant in NF1 has not been previously reported in individuals with RASopathies, but has been reported in ClinVar (Variation ID: 134887). It ha s been identified in 22/125856 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201712827). Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Ile2058Val variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 24, 2020	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.6109A>G, in exon 41 that results in an amino acid change, p.Ile2037Val. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.016% in non-Finnish European subpopulation (dbSNP rs201712827). The p.Ile2037Val change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile2037Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile2037Val change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2022	Variant summary: NF1 c.6109A>G (p.Ile2037Val) results in a conservative amino acid change which is located outside of any known functional domain or repeat of the encoded protein sequence (InterPro, UniProt). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250150 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00021), allowing no conclusion about variant significance. However, the variant is reported with a much higher occurrence in the Amish (i.e. 11/910 alleles; a frequency of 0.012), suggesting that the variant might be a benign polymorphism. The variant, c.6109A>G, has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Koczkowska_2018) or suspected RASopathy (Witkowski_2020), however in one of these reports the variant was found in a family in the proband, and not found in two affected family members, while all affected family members had a (likely) pathogenic variant, which segregated with the disease phenotype (Koczkowska_2018). In addition, the variant was reported in patients with breast cancer (Dorling_2021), but was also found in healthy controls (Bodian_2014, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2015	In silico models in agreement (benign);Other data supporting benign classification -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2019	This variant is associated with the following publications: (PMID: 32107864, 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NF1: PP2, BS1 -

NF1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.1	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.94	T;T;T
Polyphen		0.049	B;P;.
Vest4		0.34
MutPred		0.40		Gain of MoRF binding (P = 0.1041);.;.;
MVP		0.59
MPC		1.7
ClinPred		0.16	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201712827; hg19: chr17-29663677; COSMIC: COSV100648594; COSMIC: COSV100648594;