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. The variant received 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
• Publications: 24 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 17-31095310-A-C is Pathogenic according to our data. Variant chr17-31095310-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 694505.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.1A>C	p.Met1?	initiator_codon	Exon 1 of 58	NP_001035957.1
	NF1	NM_000267.4		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 57	NP_000258.1
	NF1	NM_001128147.3		c.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 1 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurofibromatosis, type 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
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
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.65	P
Vest4		0.64
MutPred		1.0		Loss of MoRF binding (P = 0.0789)
MVP		0.83
ClinPred		1.0	D
GERP RS		2.5
PromoterAI		-0.39	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.65
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: rs1060500252; hg19: chr17-29422328;