rs372169109

chr17-31337526-A-Cchr17-31337526-A-Gchr17-31337526-A-T

Variant summary

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

The NM_001042492.3(NF1):c.6586A>C(p.Thr2196Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T2196A) 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: 8.73

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 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 chr17-31337527-CT-GAGACAAAAATCATGTTTTTGTATTAATAAAATGAAAAAGATTCGATAATGGCATGGTATTACCATCCAGTTCTAAAGTGGTTTAATTCTGTGATTTGAGTACAAAGGTATGCCAGACTTGGGAGAGATAACAGAGAAATAATACCTGTTATATTCCTGGTTTGTCTACAAGCATCCTAATTTTGTATTATACAAAGCAAAGTATA is described in ClinVar as [Pathogenic]. Clinvar id is 2853294.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, NF1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6586A>C	p.Thr2196Pro	missense_variant	43/58	ENST00000358273.9
NF1	NM_000267.3	c.6523A>C	p.Thr2175Pro	missense_variant	42/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6586A>C	p.Thr2196Pro	missense_variant	43/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.28	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.25	B;D;.
Vest4		0.69
MutPred		0.36		Loss of phosphorylation at T2196 (P = 0.0062);.;.;
MVP		0.78
MPC		2.6
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.45
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-29664544;