Genetic Variant NF1:c.-173C>G (chr17-31095137-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001042492.3(NF1):c.-173C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 540,692 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 0.000080 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NF1
NM_001042492.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:4

Conservation

PhyloP100: 0.229

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BS2

High AC in GnomAd4 at 12 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.-173C>G	5_prime_UTR	Exon 1 of 58	NP_001035957.1	P21359-1
NF1	NM_000267.4		c.-173C>G	5_prime_UTR	Exon 1 of 57	NP_000258.1
NF1	NM_001128147.3		c.-173C>G	5_prime_UTR	Exon 1 of 15	NP_001121619.1	P21359-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	ENST00000358273.9	TSL:1 MANE Select	c.-173C>G	5_prime_UTR	Exon 1 of 58	ENSP00000351015.4	P21359-1
NF1	ENST00000356175.7	TSL:1	c.-173C>G	5_prime_UTR	Exon 1 of 57	ENSP00000348498.3	P21359-2
NF1	ENST00000431387.8	TSL:1	c.-173C>G	5_prime_UTR	Exon 1 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes

AF:

0.0000801

AC:

AN:

149838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00262

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

AN:

390854

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

207842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9478

American (AMR)

AF:

0.00

AC:

AN:

17380

Ashkenazi Jewish (ASJ)

AF:

0.00271

AC:

AN:

13260

East Asian (EAS)

AF:

0.0000817

AC:

AN:

24490

South Asian (SAS)

AF:

0.0000234

AC:

AN:

42662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1772

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

232568

Other (OTH)

AF:

0.000176

AC:

AN:

22778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.0000801

AC:

AN:

149838

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

73116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40762

American (AMR)

AF:

0.00

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00262

AC:

AN:

3434

East Asian (EAS)

AF:

0.000400

AC:

AN:

5006

South Asian (SAS)

AF:

0.00

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67260

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

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.:

Bravo

AF:

0.0000756

ClinVar

ClinVar submissions as Germline

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

-0.63

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.23

PromoterAI

-0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

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