17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001042492.3(NF1):c.3198-6_3198-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 587,606 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0076 ( 6 hom., cov: 0)

Exomes 𝑓: 0.0029 ( 1 hom. )

Consequence

NF1
NM_001042492.3 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.96

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 -10 ACMG points.

BP6

Variant 17-31232043-ATTT-A is Benign according to our data. Variant chr17-31232043-ATTT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1199777.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00757 (688/90874) while in subpopulation AFR AF = 0.0294 (660/22432). AF 95% confidence interval is 0.0276. There are 6 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 688 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3198-6_3198-4delTTT		splice_region_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.3198-6_3198-4delTTT		splice_region_variant, intron_variant	Intron 24 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3198-29_3198-27delTTT		intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

689

AN:

90878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

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:

0.0000209

Gnomad OTH

AF:

0.00656

GnomAD4 exome

AF:

0.00290

AC:

1441

AN:

496732

Hom.:

AF XY:

0.00289

AC XY:

755

AN XY:

261118

show subpopulations

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

African (AFR)

AF:

0.0209

AC:

210

AN:

10050

American (AMR)

AF:

0.00389

AC:

AN:

15928

Ashkenazi Jewish (ASJ)

AF:

0.00543

AC:

AN:

12152

East Asian (EAS)

AF:

0.00473

AC:

AN:

16706

South Asian (SAS)

AF:

0.00169

AC:

AN:

42690

European-Finnish (FIN)

AF:

0.00257

AC:

AN:

28754

Middle Eastern (MID)

AF:

0.00299

AC:

AN:

1670

European-Non Finnish (NFE)

AF:

0.00227

AC:

787

AN:

347066

Other (OTH)

AF:

0.00396

AC:

AN:

21716

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

114

227

341

454

568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00757

AC:

688

AN:

90874

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

312

AN XY:

42028

show subpopulations

African (AFR)

AF:

0.0294

AC:

660

AN:

22432

American (AMR)

AF:

0.00256

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:

0.00

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:

0.0000209

AC:

AN:

47878

Other (OTH)

AF:

0.00653

AC:

AN:

1226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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, single submitter

LINK: link

Submissions by phenotype

NF1-related disorder

Benign:1

Aug 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Aug 30, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over