17-31221930-G-T

Variant names:

• chr17-31221930-G-T
• rs1131691096
• ENST00000431387.8:c.1722G>T

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000431387.8(NF1):​c.1722G>T​(p.Arg574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R574G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 ENST00000431387.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.28
• Publications: 4 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 24 ACMG points.

• PS1: Transcript ENST00000431387.8 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 13 uncertain in ENST00000431387.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31221928-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1778746.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31221930-G-T is Pathogenic according to our data. Variant chr17-31221930-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 428975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000431387.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.1721+1G>T		splice_donor intron	N/A	NP_001035957.1
	NF1	NM_001128147.3		c.1722G>T	p.Arg574Ser	missense	Exon 15 of 15	NP_001121619.1
	NF1	NM_000267.4		c.1721+1G>T		splice_donor intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000431387.8	TSL:1	c.1722G>T	p.Arg574Ser	missense	Exon 15 of 15	ENSP00000412921.4
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1721+1G>T		splice_donor intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1721+1G>T		splice_donor intron	N/A	ENSP00000348498.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438746 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 715416

African (AFR) AF: 0.00 AC: 0 AN: 32576

American (AMR) AF: 0.00 AC: 0 AN: 42156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 81882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105578

Other (OTH) AF: 0.00 AC: 0 AN: 59460

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1721+1 nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18546366, 23913538). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428975). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 23913538). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 23, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1721+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the NF1 gene.<br /> This mutation was detected in an individual who met NIH diagnostic criteria for NF1 (Sabbagh A, et al.Hum. Mutat. 2013;34(11):1510-8).In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
PhyloP100		9.3
ClinPred		0.99	D
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -1

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

Other links and lift over

dbSNP: rs1131691096; hg19: chr17-29548948;