chr17-31219097-G-T

Variant names:

• chr17-31219097-G-T
• rs766748586
• NM_001042492.3:c.1620G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The NM_001042492.3(NF1):​c.1620G>T​(p.Glu540Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. E540Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.39
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• 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: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.052018434).
• BP6: Variant 17-31219097-G-T is Benign according to our data. Variant chr17-31219097-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 186553.
• BS2: High AC in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.1620G>T	p.Glu540Asp	missense	Exon 14 of 58	NP_001035957.1
	NF1	NM_000267.4		c.1620G>T	p.Glu540Asp	missense	Exon 14 of 57	NP_000258.1
	NF1	NM_001128147.3		c.1620G>T	p.Glu540Asp	missense	Exon 14 of 15	NP_001121619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1620G>T	p.Glu540Asp	missense	Exon 14 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1620G>T	p.Glu540Asp	missense	Exon 14 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.1620G>T	p.Glu540Asp	missense	Exon 14 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250708 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00000411 AC: 6 AN: 1461404 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726954

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000134 AC: 6 AN: 44652

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 27, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 18, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E540D variant (also known as c.1620G>T), located in coding exon 14 of the NF1 gene, results from a G to T substitution at nucleotide position 1620. The glutamic acid at codon 540 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000alleles tested) in our clinical cohort.<span style="background-color:initial"><span style="background-color:initial">This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. <span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">p.E540D<span style="background-color:initial">remains unclear.

Neurofibromatosis, type 1 Uncertain:1 Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Nov 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N
PhyloP100		1.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.076
Sift	Benign	0.93	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.17		Loss of disorder (P = 0.132)
MVP		0.22
MPC		0.62
ClinPred		0.14	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.25
Mutation Taster		=85/15	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: rs766748586; hg19: chr17-29546115;