17-31095311-T-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000144 in 1,385,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 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-G is Pathogenic according to our data. Variant chr17-31095311-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 426634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385328 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 683466

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31490

American (AMR) AF: 0.00 AC: 0 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1078082

Other (OTH) AF: 0.00 AC: 0 AN: 57680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 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: 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 426634). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Jul 16, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2 T>G variant in the NF1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Additionally, other p.Met1? variants (c.1 A>G, c.1_2delATinsCC, c.2 T>C, c.3 G>T, c.3 G>A) have been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1 (Stenson et al., 2014). In summary, we consider this variant to be pathogenic.

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

Jul 03, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.2T>G) is located in coding exon 1 of the NF1 gene and results from a T to G substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Multiple other alterations impacting the initiation codon (c.1A>G, c.1A>T, c.2T>C, c.3G>A, c.3G>C) have been reported in individuals diagnosed with neurofibromatosis type 1 (NF1) (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Brinckmann A et al. Electrophoresis, 2007 Dec;28:4295-301; Ko JM et al. Pediatr. Neurol., 2013 Jun;48:447-53; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Tsipi M et al. J Neurol Sci. 2018 Dec 15;395:95-105; Kang E et al. J Hum Genet. 2020 Jan;65(2):79-89). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	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		0.74
MutPred		0.99		Gain of MoRF binding (P = 6e-04)
MVP		0.75
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		-0.30	Neutral
Varity_R		0.97
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;