rs145191978

Positions:

• chr17-31219065-G-A
• chr17-31219065-G-C
• chr17-31219065-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP2 BP6 BS2_Supporting

The NM_001042492.3(NF1):​c.1588G>A​(p.Val530Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V530V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (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:5 B:4 O:1
• Conservation: PhyloP100: 6.28

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001042492.3
• PP2: Missense variant where missense usually causes diseases, NF1
• BP6: Variant 17-31219065-G-A is Benign according to our data. Variant chr17-31219065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141369.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Uncertain_significance=4}.
• BS2: High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1588G>A	p.Val530Ile	missense_variant	14/58	ENST00000358273.9
NF1	NM_000267.3	c.1588G>A	p.Val530Ile	missense_variant	14/57
NF1	NM_001128147.3	c.1588G>A	p.Val530Ile	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1588G>A	p.Val530Ile	missense_variant	14/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000797 AC: 20 AN: 251002 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135620

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

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: 0.000158

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461588 Hom.: 0 Cov.: 33 AF XY: 0.000194 AC XY: 141 AN XY: 727044

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.000247

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 23407919) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 11, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NF1 p.V530I variant was identified in an individual with pheochromocytoma who was hypertensive but did not exhibit any Neurofibromatosis type 1 symptoms; the patient also had another variant in the SDHB gene which authors reported to be pathogenic (Sjursen_2013_PMID_23407919). The variant was identified in dbSNP (ID: rs145191978) and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae and St. Jude Children's Research Hospital Clinical Genomics Lab, andas likely benign by GeneDx). The variant was identified in control databases in 21 of 282376 chromosomes at a frequency of 0.00007437 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 19 of 128982 chromosomes (freq: 0.000147), Other in 1 of 7214 chromosomes (freq: 0.000139) and African in 1 of 24882 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.V530 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Neurofibromatosis, type 1 Uncertain:1 Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	This participant was tested at multiple clinical laboratories with differing classifications. The variant was classified, most recently, as Uncertain on 04-29-2017 by GTR ID 26957.AT51 Variant was also classified as Uncertain significance and reported in October 2015 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 11, 2021	The NF1 c.1588G>A (p.Val530Ile) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-29546083-G-A?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). This variant has been observed in an individual with pheochromocytoma who also harbored a pathogenic variant in SDHB (BP5; PMID: 23407919). To our knowledge, this variant has not been reported in individuals with Neurofibromatosis type 1. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2, BP5. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 23, 2015	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 19, 2021	- -

NF1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The NF1 c.1588G>A variant is predicted to result in the amino acid substitution p.Val530Ile. This variant was identified in an individual with adrenal pheochromocytoma and hypertension, but who had no signs or symptoms of neurofibromatosis. The individual also carried a pathogenic variant in the SDHB gene (Sjursen et al. 2013. PubMed ID: 23407919). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141369/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2019

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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
Polyphen		1.0	D;D;B;.;.
Vest4		0.67, 0.52, 0.24
MVP		0.70
MPC		1.5
ClinPred		0.22	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.49

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: rs145191978; hg19: chr17-29546083; COSMIC: COSV99049900;