chr17-31221932-A-G

Variant names:

• chr17-31221932-A-G
• rs1057518904
• ENST00000431387.8:c.1724A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001128147.3(NF1):​c.1724A>G​(p.Tyr575Cys) variant causes a missense change. 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000542219: Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID:7981679; internal data).; SCV005077300: Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, resulting in exon skipping leading to a frameshift (Purandare_1994, Pros_2008).; SCV005416959: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000581237: This mutation was shown by twoseparate studiestoinduce skipping ofexon11 at the mRNA level, causinga shift in the translational reading frame, leading to premature truncation of the NF1protein(p.Ala548LeufsX13) (PurandareSM, et al. Hum. Mol. Genet. 1994;3(7):1109-15 andPros E, et al. Hum.Mutat. 2008;29(9):E173-93).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y575H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001128147.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 6.61
• Publications: 6 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000542219: Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7981679; internal data).; SCV005077300: Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, resulting in exon skipping leading to a frameshift (Purandare_1994, Pros_2008).; SCV005416959: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000581237: This mutation was shown by twoseparate studiestoinduce skipping ofexon11 at the mRNA level, causinga shift in the translational reading frame, leading to premature truncation of the NF1protein(p.Ala548LeufsX13) (PurandareSM, et al. Hum. Mol. Genet. 1994;3(7):1109-15 andPros E, et al. Hum.Mutat. 2008;29(9):E173-93).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 10 uncertain in NM_001128147.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31221931-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2736517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31221932-A-G is Pathogenic according to our data. Variant chr17-31221932-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128147.3. 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.1721+3A>G		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_001128147.3		c.1724A>G	p.Tyr575Cys	missense	Exon 15 of 15	NP_001121619.1	P21359-5
	NF1	NM_000267.4		c.1721+3A>G		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000431387.8	TSL:1	c.1724A>G	p.Tyr575Cys	missense	Exon 15 of 15	ENSP00000412921.4	P21359-5
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1721+3A>G		splice_region intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.1721+3A>G		splice_region intron	N/A	ENSP00000348498.3	P21359-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Neurofibromatosis, type 1 (9)
4	-	-	not provided (4)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Juvenile myelomonocytic leukemia (1)
1	-	-	Neurofibroma;C1861975:Cafe au lait spots, multiple (1)
1	-	-	Optic nerve glioma;C1861975:Cafe au lait spots, multiple (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Benign	0.051
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.85	T
PhyloP100		6.6
PROVEAN	Benign	1.2	N
REVEL	Benign	0.18
Sift	Benign	0.057	T
Sift4G	Benign	0.15	T
Vest4		0.47
MutPred		0.33		Gain of catalytic residue at I573 (P = 0.1473)
MVP		0.64
ClinPred		0.70	D
GERP RS		5.8
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: -1
DS_DL_spliceai		0.49		Position offset: -3

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

Other links and lift over

dbSNP: rs1057518904; hg19: chr17-29548950; COSMIC: COSV62193369;