rs267606603

chr17-31201486-G-Achr17-31201486-G-Cchr17-31201486-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):c.1260+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.22

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.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.004342723 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.8, offset of 13, new splice context is: aagGTattg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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 17-31201486-G-A is Pathogenic according to our data. Variant chr17-31201486-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31201486-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1260+1G>A		splice_donor_variant		ENST00000358273.9
NF1	NM_000267.3	c.1260+1G>A		splice_donor_variant
NF1	NM_001128147.3	c.1260+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1260+1G>A		splice_donor_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151456 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151456 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73900

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 30, 2023	This sequence change affects a donor splice site in intron 11 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10677298, 22155606; Invitae). ClinVar contains an entry for this variant (Variation ID: 356). Studies have shown that disruption of this splice site results in inclusion of 13 base pairs of intronic sequence and introduces a premature termination codon (PMID: 10677298). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2020

Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Eisenbarth 2000, Giugliano 2019); Not observed in large population cohorts (Lek 2016); Observed in individuals with clinically diagnosed neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Eisenbarth 2000, Maertens 2006, Giugliano 2019); This variant is associated with the following publications: (PMID: 31370276, 16941471, 10677298, 11409870, 22155606, 28492532, 23913538, 10712197, 25525159) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606603; hg19: chr17-29528504; COSMIC: COSV62197036;