rs1555613206

chr17-31221929-G-Achr17-31221929-G-Cchr17-31221929-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):c.1721G>A(p.Ser574Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S574G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.28

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31221929-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31221929-G-A is Pathogenic according to our data. Variant chr17-31221929-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31221929-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1721G>A	p.Ser574Asn	missense_variant, splice_region_variant	15/58	ENST00000358273.9
NF1	NM_001128147.3	c.1721G>A	p.Arg574Lys	missense_variant	15/15
NF1	NM_000267.3	c.1721G>A	p.Ser574Asn	missense_variant, splice_region_variant	15/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1721G>A	p.Ser574Asn	missense_variant, splice_region_variant	15/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 07, 2022	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 431976). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16835897, 24232412; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 574 of the NF1 protein (p.Ser574Asn). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Cafe au lait spots, multiple Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 04, 2023

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 10712197, 16835897, 24232412, 29673180, 29685074, 25486365, 30014477) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.1721G>A pathogenic mutation (also known as p.S574N), located in coding exon 15 of the NF1 gene, results from a G to A substitution at nucleotide position 1721. The amino acid change results in serine to asparagine at codon 574, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This alteration has been previously reported in multiple individuals diagnosed with neurofibromatosis type 1 (Fahsold R et al, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Lee MJ et al, Hum. Mutat. 2006 Aug; 27(8):832; Palma Milla C et al. Ann. Hum. Genet. 2018 Nov;82(6):425-436; Stella A et al. Genes (Basel) 2018 Apr;9(4)). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2016

The c.1721G>A variant (also known as p.S574N), located in coding exon 15 of the NF1 gene, results from a G to A substitution at nucleotide position 1721. The amino acid change results in serine to asparagine at codon 574, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. <span style="font-family:sans-serif,arial,verdana,trebuchet ms">This mutationhas been previously reported in multiple individuals diagnosedwithneurofibromatosistype1 (FahsoldR et al,Am. J. Hum. Genet. 2000 Mar; 66(3):790-818;Lee MJ et al,Hum.Mutat. 2006 Aug; 27(8):832)<span style="font-family:sans-serif,arial,verdana,trebuchet ms">.This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. Both the nucleotide andamino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis.Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	31
Dann	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.15	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	0.71	N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D
Sift4G	Benign	0.26	T
Vest4		0.69
MutPred		0.48		Gain of ubiquitination at R574 (P = 0.0192);
MVP		0.85
ClinPred		0.79	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555613206; hg19: chr17-29548947;