NM_001042492.3:c.60+5C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_001042492.3(NF1):c.60+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 1,539,318 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

NF1
NM_001042492.3 splice_region, intron

Scores

Splicing: ADA: 0.002538

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.945

Publications

0 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 links:

MIR4733HG (HGNC:55332): (MIR4733 host gene)

MIR4733HG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 17-31095374-C-G is Benign according to our data. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095374-C-G is described in CliVar as Likely_benign. Clinvar id is 457777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.60+5C>G	splice_region_variant, intron_variant	Intron 1 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
MIR4733HG	NR_186435.1 link	n.117G>C	non_coding_transcript_exon_variant	Exon 1 of 4
NF1	NM_000267.4 link	c.60+5C>G	splice_region_variant, intron_variant	Intron 1 of 56		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.60+5C>G	splice_region_variant, intron_variant	Intron 1 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.60+5C>G		splice_region_variant, intron_variant	Intron 1 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000577

AC:

AN:

1387350

Hom.:

Cov.:

AF XY:

0.00000584

AC XY:

AN XY:

684616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31542

American (AMR)

AF:

0.00

AC:

AN:

35648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35888

South Asian (SAS)

AF:

0.00

AC:

AN:

79120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4208

European-Non Finnish (NFE)

AF:

0.00000742

AC:

AN:

1078412

Other (OTH)

AF:

0.00

AC:

AN:

57746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67950

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Jan 29, 2020

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

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.94

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.092

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over