chr17-31232043-ATTTTTTT-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6_Very_StrongBS2_Supporting

The NM_001042492.3(NF1):c.3198-10_3198-4delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 589,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

NF1
NM_001042492.3 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 3.14

Publications

2 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: Benign. The variant received -9 ACMG points.

BP6

Variant 17-31232043-ATTTTTTT-A is Benign according to our data. Variant chr17-31232043-ATTTTTTT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 996498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 35 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3198-10_3198-4delTTTTTTT		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-10_3198-4delTTTTTTT		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NF1	ENST00000358273.9	TSL:1 MANE Select	c.3198-29_3198-23delTTTTTTT	intron	N/A	ENSP00000351015.4
NF1	ENST00000356175.7	TSL:1	c.3198-29_3198-23delTTTTTTT	intron	N/A	ENSP00000348498.3
NF1	ENST00000579081.6	TSL:1	n.3198-29_3198-23delTTTTTTT	intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes

AF:

0.000385

AC:

AN:

90908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000251

Gnomad OTH

AF:

0.00164

GnomAD4 exome

AF:

0.000303

AC:

151

AN:

498962

Hom.:

AF XY:

0.000286

AC XY:

AN XY:

262402

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

10160

American (AMR)

AF:

0.000811

AC:

AN:

16030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12224

East Asian (EAS)

AF:

0.000179

AC:

AN:

16804

South Asian (SAS)

AF:

0.000210

AC:

AN:

42944

European-Finnish (FIN)

AF:

0.0000693

AC:

AN:

28844

Middle Eastern (MID)

AF:

0.00297

AC:

AN:

1682

European-Non Finnish (NFE)

AF:

0.000258

AC:

AN:

348432

Other (OTH)

AF:

0.000412

AC:

AN:

21842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000385

AC:

AN:

90904

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

42042

show subpopulations

African (AFR)

AF:

0.000312

AC:

AN:

22460

American (AMR)

AF:

0.00148

AC:

AN:

7430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2612

East Asian (EAS)

AF:

0.00

AC:

AN:

2712

South Asian (SAS)

AF:

0.00128

AC:

AN:

2352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000251

AC:

AN:

47880

Other (OTH)

AF:

0.00163

AC:

AN:

1226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.00

Hom.:

224

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

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Jul 06, 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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over