NM_001042492.3:c.7838C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP6BS2_Supporting

The NM_001042492.3(NF1):c.7838C>T(p.Pro2613Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

BP6

Variant 17-31357059-C-T is Benign according to our data. Variant chr17-31357059-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229734.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=4}.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7838C>T	p.Pro2613Leu	missense_variant	Exon 53 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.7775C>T	p.Pro2592Leu	missense_variant	Exon 52 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.7838C>T	p.Pro2613Leu	missense_variant	Exon 53 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251078

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135730

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An NF1 c.7838C>T (p.Pro2613Leu) variant was identified at a near heterozygous allelic fraction of 43.2%, a frequency which may be consistent with germline origin. This variant has been reported in the literature as a germline variant of uncertain significance in a Japanese individual with breast cancer (Momozawa Y et al., PMID: 30287823) and as a somatic variant in colorectal cancer (Giannakis M et al., PMID: 27149842) and five times in the cancer database COSMIC in malignancies of the brain, large intestine and skin (Genomic mutation ID: COSV62208536 ). It has also been reported in the ClinVar database as a germline variant of uncertain significance by three submitters and a germline likely benign variant by one submitter (ClinVar variation ID: Variation ID: 229734). The NF1 c.7838C>T (p.Pro2613Leu) is only observed on 22/1,613,608 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. Computational predictors suggest that the variant does not impact NF1 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

not provided

Uncertain:1Benign:1

Mar 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27149842, 30287823) -

May 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7775C>T (p.P2592L) alteration is located in exon 52 (coding exon 52) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 7775, causing the proline (P) at amino acid position 2592 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 25, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P2613L variant (also known as c.7838C>T), located in coding exon 53 of the NF1 gene, results from a C to T substitution at nucleotide position 7838. The proline at codon 2613 is replaced by leucine, an amino acid with 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. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000alleles tested) in our clinical cohort. Thisamino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.P2613L remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Benign

0.88

DEOGEN2

Uncertain

0.56

D;.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.84

L;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.77

T;T;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.015

B;D;.

Vest4

0.81

MutPred

0.30

Gain of helix (P = 0.0022);.;.;

MVP

0.80

MPC

1.5

ClinPred

0.56

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over