Genetic Variant NF1:c.-237C>T (chr17-31095073-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001042492.3(NF1):c.-237C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 452,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

NF1
NM_001042492.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:4

Conservation

PhyloP100: 0.706

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BS2

High AC in GnomAd4 at 31 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	NM_001042492.3	MANE Select	c.-237C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 58	NP_001035957.1	P21359-1
NF1	NM_001042492.3	MANE Select	c.-237C>T	5_prime_UTR	Exon 1 of 58	NP_001035957.1	P21359-1
NF1	NM_000267.4		c.-237C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 57	NP_000258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	ENST00000358273.9	TSL:1 MANE Select	c.-237C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 58	ENSP00000351015.4	P21359-1
NF1	ENST00000356175.7	TSL:1	c.-237C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 57	ENSP00000348498.3	P21359-2
NF1	ENST00000431387.8	TSL:1	c.-237C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

150248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000397

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00252

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000178

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000205

AC:

AN:

302536

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

AN XY:

155398

show subpopulations

African (AFR)

AF:

0.000123

AC:

AN:

8106

American (AMR)

AF:

0.000285

AC:

AN:

10520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10158

East Asian (EAS)

AF:

0.00

AC:

AN:

24390

South Asian (SAS)

AF:

0.00130

AC:

AN:

15386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1488

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

189642

Other (OTH)

AF:

0.000366

AC:

AN:

19144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000206

AC:

AN:

150356

Hom.:

Cov.:

AF XY:

0.000218

AC XY:

AN XY:

73434

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40886

American (AMR)

AF:

0.000396

AC:

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5060

South Asian (SAS)

AF:

0.00252

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000178

AC:

AN:

67320

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000184

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Café-au-lait macules with pulmonary stenosis (1)

Neurofibromatosis-Noonan syndrome (1)

Neurofibromatosis, familial spinal (1)

Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.71

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=294/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over