chr17-31226566-C-T

Position:

• chr17-31226566-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_001042492.3(NF1):​c.2133C>T​(p.Arg711Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,613,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.582

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]

NF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-31226566-C-T is Benign according to our data. Variant chr17-31226566-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 184381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2133C>T	p.Arg711Arg	synonymous_variant	18/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2133C>T	p.Arg711Arg	synonymous_variant	18/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2133C>T	p.Arg711Arg	synonymous_variant	18/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251036 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135658

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

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: 0.000185

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1461578 Hom.: 1 Cov.: 34 AF XY: 0.000176 AC XY: 128 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.000245

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74356

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2019	Variant summary: NF1 c.2133C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 251036 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.0001 vs 0.00021), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2133C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified this variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NF1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 02, 2020	- -

Neurofibromatosis, type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2014	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.2
DANN	Benign	0.57

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: rs148085908; hg19: chr17-29553584;