rs1064794756

Positions:

• chr17-31338748-A-G
• chr17-31338748-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2 PP5_Very_Strong BP4 BP7

The NM_001042492.3(NF1):​c.6864A>G​(p.Gln2288Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,114 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.60

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]

NF1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31338748-A-G is Pathogenic according to our data. Variant chr17-31338748-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=2.61 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6864A>G	p.Gln2288Gln	synonymous_variant	46/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6801A>G	p.Gln2267Gln	synonymous_variant	45/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6864A>G	p.Gln2288Gln	synonymous_variant	46/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461114 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726908

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	This sequence change affects codon 2267 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 420870). This variant has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 21354044, 21520333; Invitae). In at least one individual the variant was observed to be de novo. -
Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Nov 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 15, 2024	This is a synonymous variant located in exon 45 of the NF1 gene. It has been reported previously in individuals with Neurofibromatosis type 1 (PMIDs: 21354044, 31694342). This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM2, PP4, PP5). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2024

Published functional studies demonstrate a damaging effect: skipping of exon 45 (referred to as exon 37 due to alternative nomenclature) (PMID: 21354044); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16870183, 22925204, 21354044) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

The c.6801A>G variant (also known as p.Q2267Q), located in coding exon 45 of the NF1 gene, results from an A to G substitution at nucleotide position 6801. This nucleotide substitution does not change the codon at 2267 which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in individuals who met NIH diagnostic criteria for neurofibromatosis type 1 (NF1) (Valero MC et al. J Mol Diagn, 2011 Mar;13:113-22; Tritto V et al. Genes (Basel), 2019 Nov;10:; Ambry internal data). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA functional studies have demonstrated that this variant is associated with in-frame skipping of coding exon 45 (Valero MC et al. J Mol Diagn, 2011 Mar;13:113-22; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1064794756; hg19: chr17-29665766;