rs1555594493

Positions:

• chr17-31095356-G-A
• chr17-31095356-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_001042492.3(NF1):​c.47G>A​(p.Arg16His) variant causes a missense change. The variant allele was found at a frequency of 0.000000721 in 1,387,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31095356-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.47G>A	p.Arg16His	missense_variant	1/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.47G>A	p.Arg16His	missense_variant	1/57		NP_000258.1
NF1	NM_001128147.3	c.47G>A	p.Arg16His	missense_variant	1/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.47G>A	p.Arg16His	missense_variant	1/58	1	NM_001042492.3	ENSP00000351015	P1
MIR4733HG	ENST00000583377.1	n.95C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387694 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 684770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	.;D;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.41, 0.41, 0.28
MutPred		0.45		Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);
MVP		0.72
MPC		0.85
ClinPred		0.99	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.50
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29422374;