ENST00000431387.8:c.1721G>A

Variant names:

• chr17-31221929-G-A
• rs1555613206
• ENST00000431387.8:c.1721G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000431387.8(NF1):​c.1721G>A​(p.Arg574Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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)
• Consequence: NF1 ENST00000431387.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.28
• 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 15 ACMG points.

• 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 17-31221929-G-A is Pathogenic according to our data. Variant chr17-31221929-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 431976.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.1721G>A	p.Ser574Asn	missense splice_region	Exon 15 of 58	NP_001035957.1	P21359-1
	NF1	NM_001128147.3		c.1721G>A	p.Arg574Lys	missense	Exon 15 of 15	NP_001121619.1	P21359-5
	NF1	NM_000267.4		c.1721G>A	p.Ser574Asn	missense splice_region	Exon 15 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000431387.8	TSL:1	c.1721G>A	p.Arg574Lys	missense	Exon 15 of 15	ENSP00000412921.4	P21359-5
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1721G>A	p.Ser574Asn	missense splice_region	Exon 15 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.1721G>A	p.Ser574Asn	missense splice_region	Exon 15 of 57	ENSP00000348498.3	P21359-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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	-	-	Cafe au lait spots, multiple (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.15	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.15	T
PhyloP100		9.3
PROVEAN	Benign	0.71	N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D
Sift4G	Benign	0.26	T
Vest4		0.69
MutPred		0.48		Gain of ubiquitination at R574 (P = 0.0192)
MVP		0.85
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.41
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

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

Other links and lift over

dbSNP: rs1555613206; hg19: chr17-29548947;