rs1135402868

Positions:

• chr17-31326013-GTCTATA-G
• chr17-31326013-GTCTATA-GTCTATATCTATA

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The ENST00000358273.9(NF1):​c.5036_5041del​(p.Ile1679_Tyr1680del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1677V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 ENST00000358273.9 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.64

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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in ENST00000358273.9
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000358273.9.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-31326013-GTCTATA-G is Pathogenic according to our data. Variant chr17-31326013-GTCTATA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31326013-GTCTATA-G is described in Lovd as [Pathogenic]. Variant chr17-31326013-GTCTATA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5036_5041del	p.Ile1679_Tyr1680del	inframe_deletion	37/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4973_4978del	p.Ile1658_Tyr1659del	inframe_deletion	36/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5036_5041del	p.Ile1679_Tyr1680del	inframe_deletion	37/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Medical Genetics, University of Parma	Feb 02, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2023	This variant, c.4973_4978del, results in the deletion of 2 amino acid(s) of the NF1 protein (p.Ile1658_Tyr1659del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10534774, 30530636; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431651). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2022	The NF1 c.5036_5041delTCTATA; p.Ile1679_Tyr1680del variant (rs1135402868), also known as 4973delTCTATA for NM_000267.3, is reported in the literature in multiple individuals with NF1 (Frayling 2019, Giugliano 2019, Maani 2019, Wu 1999), and is reported in ClinVar (Variation ID: 431651). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes an isoleucine and tyrosine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: Frayling IM et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019 Apr;56(4):209-219. PMID: 30530636. Giugliano T et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8):580. PMID: 31370276. Maani N et al. NF1 Patients Receiving Breast Cancer Screening: Insights from The Ontario High Risk Breast Screening Program. Cancers (Basel). 2019 May 22;11(5):707. PMID: 31121919. Wu R et al. Germline mutations in NF1 patients with malignancies. Genes Chromosomes Cancer. 1999 Dec;26(4):376-80. PMID: 10534774. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2022	In-frame deletion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31121919, 10534774, 30530636, 21089070, 31370276, 31776437) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2021	- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 23, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The c.4973_4978delTCTATA pathogenic mutation (also known as p.I1658_Y1659del) is located in coding exon 36 of the NF1 gene. This pathogenic mutation results from an in-frame TCTATA deletion at nucleotide positions 4973 to 4978. This results in the in-frame deletion of isoleucine and tyrosine at amino acid positions 1658 and 1659. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1 (Ambry internal data). This variant has also been observed in literature in multiple individuals and families with clinical diagnosis of NF1 (Wu R et al. Genes Chromosomes Cancer 1999;26(4):376-80); (Giugliano T et al. Genes (Basel), 2019 07;10:); (Maani N et al. Cancers (Basel), 2019 May;11:); (Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid region is well conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135402868; hg19: chr17-29653031;