17-31095311-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_001042492.3(NF1):c.2T>C(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.51

Publications

31 publications found

Variant links:

COSMIC-nc: COSV105255140

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:

MIR4733HG (HGNC:55332): (MIR4733 host gene)

MIR4733HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 117 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 31156124. Lost 0.024 part of the original CDS.

PS1

Another start lost variant in NM_001042492.3 (NF1) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-31095311-T-C is Pathogenic according to our data. Variant chr17-31095311-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 57		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 15		NP_001121619.1	P21359-5
MIR4733HG	NR_186435.1 link	n.180A>G		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1385328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683466

African (AFR)

AF:

0.00

AC:

AN:

31490

American (AMR)

AF:

0.00

AC:

AN:

35612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25118

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078082

Other (OTH)

AF:

0.00

AC:

AN:

57680

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:3

Sep 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disruption of the initiator codon has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 23668869, 23913538). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280054). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the NF1 mRNA. The next in-frame methionine is located at codon 68. -

Mar 15, 2022

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2025

NHS Central & South Genomic Laboratory Hub

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Mar 04, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31871297, 23668869, 10712197) -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Jan 16, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the NF1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in one individual from a cohort of 521 German and Turkish patients with a clinical diagnosis of neurofibromatosis type I (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.74

.;D;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-1.1

PhyloP100

4.5

PROVEAN

Uncertain

-3.1

.;D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D

Polyphen

0.96

D;D;P;.

Vest4

0.90, 0.81, 0.81

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.0069);Gain of catalytic residue at M1 (P = 0.0069);Gain of catalytic residue at M1 (P = 0.0069);Gain of catalytic residue at M1 (P = 0.0069);

MVP

0.85

ClinPred

0.99

GERP RS

2.7

PromoterAI

-0.33

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.93

gMVP

0.79

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over