NM_001042492.3:c.730+2T>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001042492.3(NF1):c.730+2T>G variant causes a splice donor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00097 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2B:2

Conservation

PhyloP100: 5.50

Publications

7 publications found

Variant links:

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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 17-31181787-T-G is Pathogenic according to our data. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181787-T-G is described in CliVar as Pathogenic. Clinvar id is 41676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.730+2T>G	splice_donor_variant, intron_variant	Intron 7 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.730+2T>G	splice_donor_variant, intron_variant	Intron 7 of 56		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.730+2T>G	splice_donor_variant, intron_variant	Intron 7 of 14		NP_001121619.1	P21359-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.730+2T>G		splice_donor_variant, intron_variant	Intron 7 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.000457

AC:

AN:

148750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000973

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000415

Gnomad ASJ

AF:

0.000875

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000429

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000791

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00558

AC:

1311

AN:

234764

AF XY:

0.00511

show subpopulations

Gnomad AFR exome

AF:

0.00824

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.00307

Gnomad EAS exome

AF:

0.00620

Gnomad FIN exome

AF:

0.00895

Gnomad NFE exome

AF:

0.00669

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000968

AC:

1382

AN:

1427330

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

715

AN XY:

710726

show subpopulations

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

African (AFR)

AF:

0.00165

AC:

AN:

32806

American (AMR)

AF:

0.00604

AC:

258

AN:

42714

Ashkenazi Jewish (ASJ)

AF:

0.000974

AC:

AN:

25664

East Asian (EAS)

AF:

0.00395

AC:

151

AN:

38276

South Asian (SAS)

AF:

0.000710

AC:

AN:

84460

European-Finnish (FIN)

AF:

0.00691

AC:

350

AN:

50678

Middle Eastern (MID)

AF:

0.00114

AC:

AN:

5246

European-Non Finnish (NFE)

AF:

0.000404

AC:

440

AN:

1088234

Other (OTH)

AF:

0.000641

AC:

AN:

59252

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.239

Heterozygous variant carriers

239

479

718

958

1197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000477

AC:

AN:

148844

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

AN XY:

72258

show subpopulations

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

African (AFR)

AF:

0.000121

AC:

AN:

41246

American (AMR)

AF:

0.000414

AC:

AN:

14490

Ashkenazi Jewish (ASJ)

AF:

0.000875

AC:

AN:

3430

East Asian (EAS)

AF:

0.000198

AC:

AN:

5050

South Asian (SAS)

AF:

0.000430

AC:

AN:

4646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000806

AC:

AN:

67010

Other (OTH)

AF:

0.00

AC:

AN:

2036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00000581

Hom.:

ExAC

AF:

0.0216

AC:

2620

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

May 03, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual via exome sequencing for cancer-susceptibility syndromes in participants with atherosclerosis phenotypes (Johnston et al., 2012); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22703879) -

Neurofibromatosis, type 1

Pathogenic:1

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 7 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with NF1-related conditions (PMID: 21354044, 22190595). ClinVar contains an entry for this variant (Variation ID: 41676). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not specified

Benign:1

Jun 18, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.98

PhyloP100

5.5

GERP RS

5.9

PromoterAI

-0.049

Neutral

(source)

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -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