Genetic Variant NF1:c.1393-32T>C (chr17-31214419-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042492.3(NF1):c.1393-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,535,034 control chromosomes in the GnomAD database, including 340,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 25785 hom., cov: 31)

Exomes 𝑓: 0.67 ( 314788 hom. )

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.807

Publications

15 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-31214419-T-C is Benign according to our data. Variant chr17-31214419-T-C is described in ClinVar as Benign. ClinVar VariationId is 257276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	NM_001042492.3	MANE Select	c.1393-32T>C	intron	N/A	NP_001035957.1	P21359-1
NF1	NM_000267.4		c.1393-32T>C	intron	N/A	NP_000258.1
NF1	NM_001128147.3		c.1393-32T>C	intron	N/A	NP_001121619.1	P21359-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	ENST00000358273.9	TSL:1 MANE Select	c.1393-32T>C	intron	N/A	ENSP00000351015.4	P21359-1
NF1	ENST00000356175.7	TSL:1	c.1393-32T>C	intron	N/A	ENSP00000348498.3	P21359-2
NF1	ENST00000431387.8	TSL:1	c.1393-32T>C	intron	N/A	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes

AF:

0.538

AC:

81601

AN:

151806

Hom.:

25794

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.720

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.768

Gnomad EAS

AF:

0.562

Gnomad SAS

AF:

0.627

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.761

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.604

GnomAD2 exomes

AF:

0.620

AC:

149631

AN:

241458

AF XY:

0.636

show subpopulations

Gnomad AFR exome

AF:

0.171

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.776

Gnomad EAS exome

AF:

0.559

Gnomad FIN exome

AF:

0.662

Gnomad NFE exome

AF:

0.697

Gnomad OTH exome

AF:

0.668

GnomAD4 exome

AF:

0.667

AC:

922993

AN:

1383112

Hom.:

314788

Cov.:

AF XY:

0.670

AC XY:

463309

AN XY:

691984

show subpopulations

African (AFR)

AF:

0.166

AC:

5330

AN:

32072

American (AMR)

AF:

0.509

AC:

22061

AN:

43304

Ashkenazi Jewish (ASJ)

AF:

0.774

AC:

19674

AN:

25412

East Asian (EAS)

AF:

0.555

AC:

21733

AN:

39166

South Asian (SAS)

AF:

0.635

AC:

52943

AN:

83370

European-Finnish (FIN)

AF:

0.656

AC:

34838

AN:

53076

Middle Eastern (MID)

AF:

0.743

AC:

2947

AN:

3964

European-Non Finnish (NFE)

AF:

0.694

AC:

725588

AN:

1045134

Other (OTH)

AF:

0.657

AC:

37879

AN:

57614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

12917

25834

38750

51667

64584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17768

35536

53304

71072

88840

<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:

0.537

AC:

81585

AN:

151922

Hom.:

25785

Cov.:

AF XY:

0.534

AC XY:

39676

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.186

AC:

7729

AN:

41496

American (AMR)

AF:

0.552

AC:

8425

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.768

AC:

2663

AN:

3468

East Asian (EAS)

AF:

0.561

AC:

2895

AN:

5164

South Asian (SAS)

AF:

0.625

AC:

3010

AN:

4814

European-Finnish (FIN)

AF:

0.656

AC:

6903

AN:

10520

Middle Eastern (MID)

AF:

0.760

AC:

222

AN:

292

European-Non Finnish (NFE)

AF:

0.704

AC:

47809

AN:

67896

Other (OTH)

AF:

0.605

AC:

1272

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1535

3070

4605

6140

7675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.620

Hom.:

5857

Bravo

AF:

0.517

Asia WGS

AF:

0.565

AC:

1960

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 1 (3)

not provided (2)

not specified (2)

Hereditary cancer-predisposing syndrome (1)

Neurofibromatosis, familial spinal (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over