rs370789267

chr17-31225143-T-Achr17-31225143-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_001042492.3(NF1):c.1894T>A(p.Cys632Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C632Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2 O:1
• Conservation: PhyloP100: 4.23

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_001042492.3
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.13229391).
• BP6: Variant 17-31225143-T-A is Benign according to our data. Variant chr17-31225143-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134883.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2, not_provided=1}.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1894T>A	p.Cys632Ser	missense_variant	17/58	ENST00000358273.9
NF1	NM_000267.3	c.1894T>A	p.Cys632Ser	missense_variant	17/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1894T>A	p.Cys632Ser	missense_variant	17/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251236 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135766

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727068

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2016	The p.C632S variant (also known as c.1894T>A), located in coding exon 17 of the NF1 gene, results from a T to A substitution at nucleotide position 1894. The cysteine at codon 632 is replaced by serine, an amino acid with dissimilar properties.This alteration was previously reported in 1/681 individuals in a healthy, ancestrally diverse cohort via genome sequencing, having been detected in 1/331European individuals in this cohort (BodianDL et al.PLoSONE2014;9(4):e94554). This variant was previously reported in the SNPDatabase as rs370789267. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.C632S remains unclear. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	See Variant Classification Assertion Criteria. -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2021	Variant summary: NF1 c.1894T>A (p.Cys632Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251898 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1894T>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been reported internally (MSH6 c.3920_3923dupATCT, p.P1309fs*11), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Benign	0.25
DEOGEN2	Uncertain	0.45	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.81
MutPred		0.44		Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;
MVP		0.57
MPC		0.85
ClinPred		0.062	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370789267; hg19: chr17-29552161;