rs1060500309

Variant names:

• chr17-31169974-C-A
• rs1060500309
• NM_001042492.3:c.563C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31169974-C-A
• chr17-31169974-C-T
• chr17-31169974-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001042492.3(NF1):​c.563C>A​(p.Ala188Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A188V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.29
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 28 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.22142208).

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.563C>A	p.Ala188Glu	missense	Exon 5 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.563C>A	p.Ala188Glu	missense	Exon 5 of 57	NP_000258.1
	NF1	NM_001128147.3		c.563C>A	p.Ala188Glu	missense	Exon 5 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.563C>A	p.Ala188Glu	missense	Exon 5 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.563C>A	p.Ala188Glu	missense	Exon 5 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.563C>A	p.Ala188Glu	missense	Exon 5 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 148712 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00713 AC: 7119 AN: 997794 Hom.: 0 Cov.: 28 AF XY: 0.00660 AC XY: 3350 AN XY: 507634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00656 AC: 153 AN: 23328

American (AMR) AF: 0.000677 AC: 27 AN: 39864

Ashkenazi Jewish (ASJ) AF: 0.00400 AC: 75 AN: 18730

East Asian (EAS) AF: 0.00226 AC: 65 AN: 28810

South Asian (SAS) AF: 0.00160 AC: 125 AN: 78090

European-Finnish (FIN) AF: 0.00195 AC: 76 AN: 38886

Middle Eastern (MID) AF: 0.00404 AC: 17 AN: 4206

European-Non Finnish (NFE) AF: 0.00873 AC: 6331 AN: 725564

Other (OTH) AF: 0.00620 AC: 250 AN: 40316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000134 AC: 2 AN: 148854 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 2 AN XY: 72762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000245 AC: 1 AN: 40750

American (AMR) AF: 0.00 AC: 0 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4582

South Asian (SAS) AF: 0.000239 AC: 1 AN: 4178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67390

Other (OTH) AF: 0.00 AC: 0 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	1	-	Hereditary pheochromocytoma-paraganglioma (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.52
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.013	B
Vest4		0.37
MutPred		0.41		Gain of solvent accessibility (P = 0.0145)
MVP		0.67
MPC		0.80
ClinPred		0.28	T
GERP RS		3.6
Varity_R		0.092
gMVP		0.32
Mutation Taster		=70/30	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: rs1060500309; hg19: chr17-29496992; COSMIC: COSV107423962;