17-31232070-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

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:1B:2

Conservation

PhyloP100: 0.140

Publications

2 publications found

Variant links:

COSMIC-nc: COSV62198041

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

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3198-3C>T		splice_region_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.3198-3C>T		splice_region_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 link	c.3198-3C>T		splice_region_variant, intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

AF:

0.0476

AC:

1065

AN:

22372

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0198

AC XY:

1303

AN XY:

65742

show subpopulations

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

African (AFR)

AF:

0.0119

AC:

AN:

3372

American (AMR)

AF:

0.0263

AC:

102

AN:

3884

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3462

East Asian (EAS)

AF:

0.00837

AC:

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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.331

Heterozygous variant carriers

156

311

467

622

778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0476

AC:

1065

AN:

22374

Hom.:

Cov.:

AF XY:

0.0437

AC XY:

462

AN XY:

10566

show subpopulations

⚠️ 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:

AN:

2010

Ashkenazi Jewish (ASJ)

AF:

0.0537

AC:

AN:

652

East Asian (EAS)

AF:

0.0421

AC:

AN:

712

South Asian (SAS)

AF:

0.0258

AC:

AN:

698

European-Finnish (FIN)

AF:

0.0243

AC:

AN:

906

Middle Eastern (MID)

AF:

0.0882

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0569

AC:

658

AN:

11558

Other (OTH)

AF:

0.0337

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.359

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.6

(source)

DANN

Benign

0.54

PhyloP100

0.14

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over