chr17-31225134-G-A

Variant names:

• chr17-31225134-G-A
• rs199474738
• NM_001042492.3:c.1885G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_001042492.3(NF1):​c.1885G>A​(p.Gly629Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000185028: In addition, this alteration has been shown to activate a strong alternate splice acceptor site, resulting in partial exon skipping and a translational frameshift (41 nucleotide deletion) (Ars E et al. J. Med. Genet. 2003" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G629A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:5
• Conservation: PhyloP100: 5.25
• Publications: 47 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000185028: In addition, this alteration has been shown to activate a strong alternate splice acceptor site, resulting in partial exon skipping and a translational frameshift (41 nucleotide deletion) (Ars E et al. J. Med. Genet. 2003; 40:e82; Pros E et al. Hum. Mutat. 2008;29:E173-93; Welander J et al. Hum. Mol. Genet. 2012; 21:5406-16; Sabbagh A, et al. Hum. Mutat. 2013;34(11):1510-8).; SCV000260849: Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12807981, 15863657, 18546366, 23913538; internal data).; SCV002556408: PS3; SCV005416648: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005908094: Functional analysis demonstrated that this mutation creates a novel acceptor splice site, leading to aberrant splicing and a truncated protein product (PMID: 12807981, 15863657, 18546366, 23913538).; SCV000604466: Experimental evidences support that this missense variant leads to the creation of an acceptor splice site resulting in a transcript lacking 41 nucleotides in exon 17, leading to a frameshift in the protein (Ars 2003, Pros 2008).; SCV004119942: Functional studies indicate this variant results in aberrant splicing resulting in a frameshift and premature protein truncation (Table S1 - Pros et al. 2008. PubMed ID: 18546366; Ars et al. 2003. PubMed ID: 12807981).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 30 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31225134-G-A is Pathogenic according to our data. Variant chr17-31225134-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown 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.1885G>A	p.Gly629Arg	missense	Exon 17 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.1885G>A	p.Gly629Arg	missense	Exon 17 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1885G>A	p.Gly629Arg	missense	Exon 17 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.1885G>A	p.Gly629Arg	missense	Exon 17 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.1885G>A		non_coding_transcript_exon	Exon 17 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251196 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Neurofibromatosis, type 1 (14)
3	-	-	not provided (4)
1	-	-	Gastric cancer (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis (1)
1	-	-	NF1-related disorder (1)
1	-	-	not specified (1)
-	-	-	Giant cell glioblastoma (1)
-	-	-	Neoplasm (1)
-	-	-	Neurofibromatosis, type 1;C0553586:Café-au-lait macules with pulmonary stenosis;C2931482:Neurofibromatosis-Noonan syndrome (1)
-	-	-	Pilocytic astrocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.37
Sift	Benign	0.059	T
Sift4G	Benign	0.66	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.46		Loss of catalytic residue at V630 (P = 0.0225)
MVP		0.79
MPC		0.82
ClinPred		0.69	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.59
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.83		Position offset: -39

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

Other links and lift over

dbSNP: rs199474738; hg19: chr17-29552152; COSMIC: COSV62198667; COSMIC: COSV62198667;