17-31249052-A-G

Variant names:

• chr17-31249052-A-G
• rs786201844
• NM_001042492.3:c.4043A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001042492.3(NF1):​c.4043A>G​(p.His1348Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.43

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Ras-GAP (size 216) in uniprot entity NF1_HUMAN there are 42 pathogenic changes around while only 3 benign (93%) 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27015805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4043A>G	p.His1348Arg	missense_variant	Exon 30 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4043A>G	p.His1348Arg	missense_variant	Exon 30 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4043A>G	p.His1348Arg	missense_variant	Exon 30 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1348 of the NF1 protein (p.His1348Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184987). -

Hereditary cancer-predisposing syndrome Uncertain:1

May 23, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1348R variant (also known as c.4043A>G), located in coding exon 30 of the NF1 gene, results from an A to G substitution at nucleotide position 4043. The histidine at codon 1348 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort (includes this individual).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance ofp.H1348Rremains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;.;D
Eigen	Benign	-0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.28	N;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.47
MutPred		0.49		Gain of MoRF binding (P = 0.0452);Gain of MoRF binding (P = 0.0452);.;
MVP		0.76
MPC		0.85
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.40
gMVP		0.36

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: rs786201844; hg19: chr17-29576070; COSMIC: COSV62224767;