17-31095311-T-A

Variant names:

• chr17-31095311-T-A
• rs886041346
• NM_001042492.3:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_001042492.3(NF1):​c.2T>A​(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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NF1 NM_001042492.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 4.51
• Publications: 31 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 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-A is Pathogenic according to our data. Variant chr17-31095311-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547562.

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.2T>A	p.Met1?	start_lost	Exon 1 of 58	NP_001035957.1
	NF1	NM_000267.4		c.2T>A	p.Met1?	start_lost	Exon 1 of 57	NP_000258.1
	NF1	NM_001128147.3		c.2T>A	p.Met1?	start_lost	Exon 1 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.2T>A	p.Met1?	start_lost	Exon 1 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4 Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the NF1 mRNA. The next in-frame methionine is located at codon 68. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 547562). For these reasons, this variant has been classified as Pathogenic.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 25, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 20, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the NF1 gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.72
MutPred		0.99		Gain of MoRF binding (P = 0.0044)
MVP		0.75
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.96
gMVP		0.89
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs886041346; hg19: chr17-29422329;