rs1555535027

Variant names:

• chr17-31338716-T-TG
• rs1555535027
• NM_001042492.3:c.6833dupG

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_001042492.3(NF1):c.6833dupG (p.Cys2278TrpfsTer6) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.25). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.25
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 14 points.

• PVS1: Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 46 of 58) at amino acid 2278 of 2839, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~2282 amino acids (557 amino acids lost).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00122) — PM2 moderate.
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.6833dupG	p.Cys2278TrpfsTer6	frameshift	Exon 46 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.6770dupG	p.Cys2257TrpfsTer6	frameshift	Exon 45 of 57	NP_000258.1	P21359-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.6833dupG	p.Cys2278TrpfsTer6	frameshift	Exon 46 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.6770dupG	p.Cys2257TrpfsTer6	frameshift	Exon 45 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.*1998dupG		3_prime_UTR	Exon 46 of 58	ENSP00000462408.2	J3KSB5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD4 exome					30
GnomAD4 genome					32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neurofibromatosis, type 1 (4)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
Mutation Taster	N/A	disease causing (ClinVar)	0/200
PhyloP100	Pathogenic	-	9.2

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555535027;

hg19: chr17-29665734;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar