chr17-31200595-G-A

Variant names:

• chr17-31200595-G-A
• rs1131691118
• NM_001042492.3:c.1062G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.1062G>A​(p.Lys354Lys) variant causes a splice region, synonymous 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002573220: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID:18546366)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.21
• Publications: 3 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002573220: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 18546366).; SCV003915014: Located at the last nucleotide of the exon, and demonstrated to result in abnormal splicing leading to an in-frame deletion of the adjacent exon (Fahsold et al., 2000; Smith et al., 2006; Pros et al., 2008)
• 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 17-31200595-G-A is Pathogenic according to our data. Variant chr17-31200595-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428998.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.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 57	NP_000258.1
	NF1	NM_001128147.3		c.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 15	NP_001121619.1	P21359-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.1062G>A	p.Lys354Lys	splice_region synonymous	Exon 9 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Neurofibromatosis, type 1 (5)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.85
PhyloP100		9.2
PromoterAI		-0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: 0

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

Other links and lift over

dbSNP: rs1131691118; hg19: chr17-29527613;