NM_001042492.3:c.1062G>A

Variant names:

• chr17-31200595-G-A
• rs1131691118
• NM_001042492.3:c.1062G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.1062G>A​(p.Lys354Lys) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.21

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31200595-G-A is Pathogenic according to our data. Variant chr17-31200595-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31200595-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1062G>A	p.Lys354Lys	splice_region_variant, synonymous_variant	Exon 9 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1062G>A	p.Lys354Lys	splice_region_variant, synonymous_variant	Exon 9 of 57		NP_000258.1
NF1	NM_001128147.3	c.1062G>A	p.Lys354Lys	splice_region_variant, synonymous_variant	Exon 9 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1062G>A	p.Lys354Lys	splice_region_variant, synonymous_variant	Exon 9 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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:5

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 18546366). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.82). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000428998). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 25, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 354 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 29673180). ClinVar contains an entry for this variant (Variation ID: 428998). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 9, but is expected to preserve the integrity of the reading-frame (PMID: 10712197, 18546366). For these reasons, this variant has been classified as Pathogenic. -

Jul 30, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 10, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Observed in patients with NF1-related clinical features (Fahsold et al., 2000; Pros et al., 2008); Located at the last nucleotide of the exon, and demonstrated to result in abnormal splicing leading to an in-frame deletion of the adjacent exon (Fahsold et al., 2000; Smith et al., 2006; Pros et al., 2008); This variant is associated with the following publications: (PMID: 25525159, 16825284, 10712197, 18546366, 29673180, 9536098, 11967553, 17576681) -

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

Jun 06, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1062G>A variant (also known as p.K354K), located in coding exon 9 of the NF1 gene, results from a G to A substitution at nucleotide position 1062. This nucleotide substitution does not change the lysine at codon 354. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This variant was shown to have an effect on splicing at the mRNA level resulting in the in-frame skipping of exon 9. In addition, this variant was found in one individual who met diagnostic criteria and another individual whose phenotype was clinically suspicious for neurofibromatosis type 1 (Fahsold et al., Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Pros et al., Hum. Mutat. 2008 Sep; 29(9):E173-93). 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
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		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: rs1131691118; hg19: chr17-29527613;