chr17-31338716-T-TG

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		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).
	PM2Absent/extremely low in population databases		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.
	PP5Reputable source reports pathogenic		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	Prot: NP_001035957.1 UniProt:
	NF1 NM_000267.4		c.6770dupG p.Cys2257TrpfsTer6	frameshift	Exon 45 of 57	Prot: NP_000258.1 UniProt:

NF1 NM_001042492.3

MANE Select

HGVSc / HGVSpc.6833dupGp.Cys2278TrpfsTer6

Exon rankExon 46 of 58

frameshift

Prot: NP_001035957.1UniProt: P21359-1

NF1 NM_000267.4

HGVSc / HGVSpc.6770dupGp.Cys2257TrpfsTer6

Exon rankExon 45 of 57

frameshift

Prot: NP_000258.1UniProt: P21359-2

Ensembl Transcripts

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

NF1 ENST00000358273.9

TSL:1MANE Select

HGVSc / HGVSpc.6833dupGp.Cys2278TrpfsTer6

Exon rankExon 46 of 58

frameshift

Prot: ENSP00000351015.4UniProt: P21359-1

NF1 ENST00000356175.7

TSL:1

HGVSc / HGVSpc.6770dupGp.Cys2257TrpfsTer6

Exon rankExon 45 of 57

frameshift

Prot: ENSP00000348498.3UniProt: P21359-2

NF1 ENST00000579081.6

TSL:1

HGVSc / HGVSpn.*1998dupG

Exon rankExon 46 of 58

3_prime_UTR

Prot: ENSP00000462408.2UniProt: 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	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov: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 pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	9.2

Showing 2 of 2 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555535027;

hg19: chr17-29665734;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar