rs1060500252

Variant names:

• chr17-31095310-A-C
• rs1060500252
• NM_001042492.3:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-31095310-A-C
• chr17-31095310-A-G
• chr17-31095310-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. 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)
• Consequence: NF1 NM_001042492.3 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.60

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

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 21 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 [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31095310-A-C is Pathogenic according to our data. Variant chr17-31095310-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 694505.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	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 57		NP_000258.1
NF1	NM_001128147.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 15		NP_001121619.1
MIR4733HG	NR_186435.1	n.181T>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	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

-

Medical Molecular Genetics Department, National Research Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32154576, 31776437, 34080803, 38596211) -

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

Dec 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the NF1 gene and results from a A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in individuals with features consistent with neurofibromatosis type 1 (Kang et al. J Hum Genet 2020 Jan;65(2):79-89; Abdel-Aziz et al. Mol Genet Genomic Med 2021 Dec;9(12):e1631; Mudau et al. Front Genet 2024 Mar;15:1331278). 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 variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	.;D;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.6	.;N;N;N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.65	P;D;B;.
Vest4		0.64, 0.60, 0.69
MutPred		1.0		Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);
MVP		0.83
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.65

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

Other links and lift over

dbSNP: rs1060500252; hg19: chr17-29422328;