rs1060500276

Variant names:

• chr17-31233143-CAAT-C
• rs1060500276
• NM_001042492.3:c.3639_3641delAAT

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001042492.3(NF1):​c.3639_3641delAAT​(p.Met1214del) variant causes a disruptive 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 (★★). ClinVar reports functional evidence for this variant: "SCV000542040: Experimental studies have shown that this variant affects NF1 function (PMID:26635368)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1213T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.91
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000542040: Experimental studies have shown that this variant affects NF1 function (PMID: 26635368).; SCV005879413: Functional studies demonstrate that this variant disrupts interactions with the NF1 binding partner protein SPRED1 (Dunzendorfer-Matt 2016, Hirata 2016). PMID: 27313208. PMID: 26635368.; SCV002613728: Functional studies have also demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1 (Hirata Y et al. J Biol Chem, 2016 Feb;291:3124-34; Dunzendorfer-Matt T et al. Proc Natl Acad Sci U S A, 2016 07;113:7497-502).; SCV005400699: Experimental studies have demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1, which functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product (Hirata Y, et al., 2016).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001042492.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-31233143-CAAT-C is Pathogenic according to our data. Variant chr17-31233143-CAAT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 404465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.3639_3641delAAT		non_coding_transcript_exon	Exon 27 of 58	ENSP00000462408.2	J3KSB5

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neurofibromatosis, type 1 (4)
4	-	-	not provided (4)
2	-	-	Neurofibromatosis-Noonan syndrome (2)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

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

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

Other links and lift over

dbSNP: rs1060500276; hg19: chr17-29560161;