17-31337365-C-G

Variant names:

• chr17-31337365-C-G
• rs374014162
• NM_001042492.3:c.6428-3C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):​c.6428-3C>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000688 in 1,452,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.73
• Publications: 2 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), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• 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: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31337365-C-G is Pathogenic according to our data. Variant chr17-31337365-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 816775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6428-3C>G		splice_region_variant, intron_variant	Intron 42 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.6365-3C>G		splice_region_variant, intron_variant	Intron 41 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6428-3C>G		splice_region_variant, intron_variant	Intron 42 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452954 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104108

Other (OTH) AF: 0.00 AC: 0 AN: 60066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2020

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 41 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 18546366, 24232412, 30308447; Invitae). This variant is also known as c.6428-3C>G. ClinVar contains an entry for this variant (Variation ID: 816775). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 18546366, 24232412). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in skipping of exon 42 (Pros 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 18546366, 24232412, 32126153, 30308447) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Benign	0.92
PhyloP100		3.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: 1
DS_AL_spliceai		0.74		Position offset: 3

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

Other links and lift over

dbSNP: rs374014162; hg19: chr17-29664383;