17-31201405-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001042492.3(NF1):c.1186-6C>T variant causes a splice region, splice polypyrimidine tract, 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003714

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.243

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-31201405-C-T is Benign according to our data. Variant chr17-31201405-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 457522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31201405-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAdExome at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
NF1	NM_001042492.3 linkuse as main transcript	c.1186-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000358273.9
NF1	NM_000267.3 linkuse as main transcript	c.1186-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
NF1	NM_001128147.3 linkuse as main transcript	c.1186-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.1186-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

140660

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000155

Gnomad OTH

AF:

0.000514

GnomAD3 exomes

AF:

0.000669

AC:

158

AN:

236306

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

128662

show subpopulations

Gnomad AFR exome

AF:

0.000744

Gnomad AMR exome

AF:

0.000277

Gnomad ASJ exome

AF:

0.00105

Gnomad EAS exome

AF:

0.000528

Gnomad SAS exome

AF:

0.000428

Gnomad FIN exome

AF:

0.000844

Gnomad NFE exome

AF:

0.000791

Gnomad OTH exome

AF:

0.000710

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000131

AC:

188

AN:

1435578

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

713928

show subpopulations

Gnomad4 AFR exome

AF:

0.000808

Gnomad4 AMR exome

AF:

0.000978

Gnomad4 ASJ exome

AF:

0.000275

Gnomad4 EAS exome

AF:

0.000103

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000674

Gnomad4 OTH exome

AF:

0.000220

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000227

AC:

AN:

140660

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

68040

show subpopulations

Gnomad4 AFR

AF:

0.000185

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00164

Gnomad4 NFE

AF:

0.000155

Gnomad4 OTH

AF:

0.000514

Alfa

AF:

0.0201

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 18, 2022

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

0.42

Dann

Benign

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.044

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over