rs766011053

chr17-31200476-C-Achr17-31200476-C-Gchr17-31200476-C-T

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.943C>A(p.Gln315Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. Q315H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.27446058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.943C>A	p.Gln315Lys	missense_variant	9/58	ENST00000358273.9
NF1	NM_000267.3	c.943C>A	p.Gln315Lys	missense_variant	9/57
NF1	NM_001128147.3	c.943C>A	p.Gln315Lys	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.943C>A	p.Gln315Lys	missense_variant	9/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.017
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
Polyphen		0.015	B;B;B;.
Vest4		0.67, 0.62, 0.68
MutPred		0.40		Gain of ubiquitination at Q315 (P = 0.017);Gain of ubiquitination at Q315 (P = 0.017);Gain of ubiquitination at Q315 (P = 0.017);Gain of ubiquitination at Q315 (P = 0.017);
MVP		0.82
MPC		0.90
ClinPred		0.46	T
GERP RS		5.4
Varity_R		0.57
gMVP		0.44

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: rs766011053; hg19: chr17-29527494;