17-31232812-C-T

Variant names:

• chr17-31232812-C-T
• rs1555614963
• NM_001042492.3:c.3427C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.3427C>T​(p.His1143Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 17) in uniprot entity NF1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31232812-C-T is Pathogenic according to our data. Variant chr17-31232812-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 457648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232812-C-T is described in Lovd as [Pathogenic]. Variant chr17-31232812-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3427C>T	p.His1143Tyr	missense_variant	Exon 26 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3427C>T	p.His1143Tyr	missense_variant	Exon 26 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3427C>T	p.His1143Tyr	missense_variant	Exon 26 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1143 of the NF1 protein (p.His1143Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type I (PMID: 12807981, 18546366, 30530636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 457648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 12807981, 30530636). For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

Jul 07, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3427C>T variant (also known as p.H1143Y), located in coding exon 26 of the NF1 gene, results from a C to T substitution at nucleotide position 3427. The histidine at codon 1143 is replaced by tyrosine, an amino acid with similar properties. The variant has been detected in multiple individuals with neurofibromatosis type 1 (Ars E et al. J Med Genet, 2003 Jun;40:e82; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in partial skipping of exon 26 (Ars E et al. J Med Genet, 2003 Jun;40:e82; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.94	P;P;.
Vest4		0.86
MutPred		0.41		Loss of disorder (P = 0.0455);Loss of disorder (P = 0.0455);.;
MVP		0.75
MPC		1.7
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.41
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555614963; hg19: chr17-29559830;