Genetic Variant NF1:c.3198-13_3198-4delTTTTTTTTTT (chr17-31232043-ATTTTTTTTTT-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP6_ModerateBS2_Supporting

The NM_001042492.3(NF1):c.3198-13_3198-4delTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
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: Unknown 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 -3 ACMG points.

BP6

Variant 17-31232043-ATTTTTTTTTT-A is Benign according to our data. Variant chr17-31232043-ATTTTTTTTTT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3048484.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3198-13_3198-4delTTTTTTTTTT		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.3198-13_3198-4delTTTTTTTTTT		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	ENST00000358273.9	TSL:1 MANE Select	c.3198-29_3198-20delTTTTTTTTTT	intron	N/A	ENSP00000351015.4	P21359-1
NF1	ENST00000356175.7	TSL:1	c.3198-29_3198-20delTTTTTTTTTT	intron	N/A	ENSP00000348498.3	P21359-2
NF1	ENST00000579081.6	TSL:1	n.3198-29_3198-20delTTTTTTTTTT	intron	N/A	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

90908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000424

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000835

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000341

AC:

AN:

499010

Hom.:

AF XY:

0.0000343

AC XY:

AN XY:

262428

show subpopulations

African (AFR)

AF:

0.000295

AC:

AN:

10162

American (AMR)

AF:

0.00

AC:

AN:

16036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12226

East Asian (EAS)

AF:

0.000119

AC:

AN:

16804

South Asian (SAS)

AF:

0.0000233

AC:

AN:

42948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1682

European-Non Finnish (NFE)

AF:

0.0000287

AC:

AN:

348458

Other (OTH)

AF:

0.0000458

AC:

AN:

21848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000110

AC:

AN:

90904

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

42042

show subpopulations

African (AFR)

AF:

0.000178

AC:

AN:

22460

American (AMR)

AF:

0.000135

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:

0.000425

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:

0.0000835

AC:

AN:

47880

Other (OTH)

AF:

0.00

AC:

AN:

1226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

NF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-31232043-ATTTTTTTTTTTTTTT-ATTTTT

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

Computational scores

Splicing

Publications

Other links and lift over