NM_001042492.3:c.3198-3C>T

Variant names:

• chr17-31232070-C-T
• rs777759972
• NM_001042492.3:c.3198-3C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001042492.3(NF1):​c.3198-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.048 (0 hom., cov: 0)
  • Exomes 𝑓: 0.019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 0.001181
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.140
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-31232070-C-T is Benign according to our data. Variant chr17-31232070-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457630.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3198-3C>T		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-3C>T		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.3198-3C>T		splice_region intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-3C>T		splice_region intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-3C>T		splice_region intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 1065 AN: 22372 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0537

Gnomad EAS AF: 0.0419

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0882

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0337

GnomAD2 exomes AF: 0.00502 AC: 154 AN: 30650 AF XY: 0.00525

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00363

Gnomad EAS exome AF: 0.00505

Gnomad FIN exome AF: 0.00321

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00749

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0194 AC: 2456 AN: 126416 Hom.: 0 Cov.: 3 AF XY: 0.0198 AC XY: 1303 AN XY: 65742

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0119 AC: 40 AN: 3372

American (AMR) AF: 0.0263 AC: 102 AN: 3884

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3462

East Asian (EAS) AF: 0.00837 AC: 64 AN: 7646

South Asian (SAS) AF: 0.0763 AC: 380 AN: 4978

European-Finnish (FIN) AF: 0.0113 AC: 100 AN: 8824

Middle Eastern (MID) AF: 0.0104 AC: 5 AN: 480

European-Non Finnish (NFE) AF: 0.0182 AC: 1595 AN: 87604

Other (OTH) AF: 0.0201 AC: 124 AN: 6166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0476 AC: 1065 AN: 22374 Hom.: 0 Cov.: 0 AF XY: 0.0437 AC XY: 462 AN XY: 10566

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0364 AC: 195 AN: 5360

American (AMR) AF: 0.0388 AC: 78 AN: 2010

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 35 AN: 652

East Asian (EAS) AF: 0.0421 AC: 30 AN: 712

South Asian (SAS) AF: 0.0258 AC: 18 AN: 698

European-Finnish (FIN) AF: 0.0243 AC: 22 AN: 906

Middle Eastern (MID) AF: 0.0882 AC: 3 AN: 34

European-Non Finnish (NFE) AF: 0.0569 AC: 658 AN: 11558

Other (OTH) AF: 0.0337 AC: 11 AN: 326

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Jun 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 08, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 23, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.54
PhyloP100		0.14
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777759972; hg19: chr17-29559088; COSMIC: COSV62198041;