Variant 17-31221401-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001042492.3(NF1):c.1642-449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.791

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-31221401-A-G is Pathogenic according to our data. Variant chr17-31221401-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31221401-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
NF1	NM_001042492.3 linkuse as main transcript	c.1642-449A>G	intron_variant	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3 linkuse as main transcript	c.1642-449A>G	intron_variant		NP_000258.1
NF1	NM_001128147.3 linkuse as main transcript	c.1642-449A>G	intron_variant		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.1642-449A>G		intron_variant		1	NM_001042492.3	ENSP00000351015	P1	P21359-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Published functional studies demonstrate a damaging effect: aberrant splicing, leading to an insertion and frameshift effect (Douben et al., 2022; Koczkowska et al., 2023); In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 16479075, 23668869, 36251260, 37186028) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	NF1: PM2, PP4:Moderate, PS4:Moderate, PP3 -

Neurofibromatosis, type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2021

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site, leading to altered splicing and introduction of a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 216394). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 16479075, 23668869; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.1642-449A>G intronic variant results from an A to G substitution 449 nucleotides upstream from coding exon 15 in the NF1 gene. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with neurofibromatosis type 1 (NF1)(Ambry internal data). This variant has been detected in individuals meeting diagnostic criteria for NF1 and RNA studies reported to result in aberrant splicing (Jeong SY et al. J Korean Med Sci, 2006 Feb;21:107-12; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Douben HCW et al. Hum Mutat, 2022 Dec;43:2130-2140; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. This variant was not reported in population-based 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

-0.82

CADD

Pathogenic

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_AG_spliceai