rs551568608

Positions:

• chr17-31155970-CT-C
• chr17-31155970-CT-CTT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001042492.3(NF1):​c.61-4del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,531,678 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: NF1 NM_001042492.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.175

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 17-31155970-CT-C is Benign according to our data. Variant chr17-31155970-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 322566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31155970-CT-C is described in Lovd as [Benign]. Variant chr17-31155970-CT-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.61-4del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.61-4del		splice_polypyrimidine_tract_variant, intron_variant			NP_000258.1
NF1	NM_001128147.3	c.61-4del		splice_polypyrimidine_tract_variant, intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.61-4del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 297 AN: 145224 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.000503

GnomAD4 exome AF: 0.00221 AC: 3062 AN: 1386372 Hom.: 6 Cov.: 33 AF XY: 0.00213 AC XY: 1467 AN XY: 689360

Gnomad4 AFR exome AF: 0.000497

Gnomad4 AMR exome AF: 0.000193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000546

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00204 AC: 297 AN: 145306 Hom.: 2 Cov.: 31 AF XY: 0.00235 AC XY: 166 AN XY: 70642

Gnomad4 AFR AF: 0.000583

Gnomad4 AMR AF: 0.000274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.00223

Gnomad4 OTH AF: 0.000498

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.00122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NF1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	This variant is associated with the following publications: (PMID: 15060124, 18592002) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2017	Variant summary: The NF1 c.61-4delT variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 316/77450 control chromosomes from ExAC, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.016349 (79/4832). This frequency is about 78 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. One patient with neurofibromatosis type 1 carried this variant along with another likely pathogenic splice mutation (c.1642-2A>G), indicating that the variant was not the cause of disease (Mattocks_JMG_2004). In addition, one clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as benign. -

Neurofibromatosis, type 1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 17, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Neurofibromatosis-Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neurofibromatosis, familial spinal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Café-au-lait macules with pulmonary stenosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs551568608; hg19: chr17-29482988;