rs1057518904

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-31221932-A-C
• chr17-31221932-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001128147.3(NF1):​c.1724A>C​(p.Tyr575Ser) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). 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 criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.61
• Publications: 0 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 10 ACMG points.

• 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-C is Pathogenic according to our data. Variant chr17-31221932-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1383029.Status of the report is criteria_provided_single_submitter, 1 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>C		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_001128147.3		c.1724A>C	p.Tyr575Ser	missense	Exon 15 of 15	NP_001121619.1	P21359-5
	NF1	NM_000267.4		c.1721+3A>C		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>C	p.Tyr575Ser	missense	Exon 15 of 15	ENSP00000412921.4	P21359-5
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1721+3A>C		splice_region intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.1721+3A>C		splice_region intron	N/A	ENSP00000348498.3	P21359-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.68
Eigen	Benign	-0.28
Eigen_PC	Benign	0.038
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.92	T
PhyloP100		6.6
PROVEAN	Benign	4.5	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.66
MutPred		0.35		Loss of stability (P = 0.0504)
MVP		0.58
ClinPred		0.26	T
GERP RS		5.8
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		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;