rs587782772

Variant names:

• chr17-31159046-C-A
• rs587782772
• NM_001042492.3:c.241C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31159046-C-A
• chr17-31159046-C-G
• chr17-31159046-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Moderate BP6 BS2_Supporting

The NM_001042492.3(NF1):​c.241C>A​(p.Leu81Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,455,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L81V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 4.47
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 30 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.19477826).
• BP6: Variant 17-31159046-C-A is Benign according to our data. Variant chr17-31159046-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142858.
• BS2: High AC in GnomAdExome4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.241C>A	p.Leu81Ile	missense	Exon 3 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.241C>A	p.Leu81Ile	missense	Exon 3 of 57	NP_000258.1
	NF1	NM_001128147.3		c.241C>A	p.Leu81Ile	missense	Exon 3 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.241C>A	p.Leu81Ile	missense	Exon 3 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.241C>A	p.Leu81Ile	missense	Exon 3 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.241C>A	p.Leu81Ile	missense	Exon 3 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250874 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455882 Hom.: 0 Cov.: 28 AF XY: 0.0000110 AC XY: 8 AN XY: 724618

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60154

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	-	1	Neurofibromatosis, type 1 (1)
-	1	-	Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.12
Sift	Benign	0.039	D
Sift4G	Benign	0.40	T
Polyphen		0.36	B
Vest4		0.51
MutPred		0.20		Gain of methylation at K77 (P = 0.0778)
MVP		0.29
MPC		0.80
ClinPred		0.43	T
GERP RS		5.1
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.25
Mutation Taster		=81/19	polymorphism

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: rs587782772; hg19: chr17-29486064;