rs1555614816

Variant names:

• chr17-31232069-T-TC
• rs1555614816
• NM_001042492.3:c.3198-3dupC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The NM_001042492.3(NF1):​c.3198-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.140

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 -10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013732394 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: ttttttttttttttttccAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 17-31232069-T-TC is Benign according to our data. Variant chr17-31232069-T-TC is described in ClinVar as [Likely_benign]. Clinvar id is 220995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-3dupC		splice_acceptor_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-3dupC		splice_acceptor_variant, intron_variant	Intron 24 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-4_3198-3insC		splice_region_variant, intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.000589 AC: 86 AN: 145986 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000541

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000745

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 31 AN: 1161242 Hom.: 0 Cov.: 3 AF XY: 0.0000309 AC XY: 18 AN XY: 581714

Gnomad4 AFR exome AF: 0.000406

Gnomad4 AMR exome AF: 0.0000659

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000590

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000796

Gnomad4 OTH exome AF: 0.000123

GnomAD4 genome AF: 0.000616 AC: 90 AN: 146056 Hom.: 0 Cov.: 0 AF XY: 0.000603 AC XY: 43 AN XY: 71290

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.000541

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000745

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000518 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NF1-related disorder Benign:1

Jan 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neurofibromatosis, type 1 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 24, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1555614816; hg19: chr17-29559087;