Genetic Variant NM_001042492.3:c.-243_-242dupCC (chr17-31095064-T-TCC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001042492.3(NF1):c.-243_-242dupCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.545

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS2

High AC in GnomAdExome4 at 32 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.-243_-242dupCC	5_prime_UTR_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.-243_-242dupCC	5_prime_UTR_variant	Exon 1 of 57		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.-243_-242dupCC	5_prime_UTR_variant	Exon 1 of 15		NP_001121619.1	P21359-5
MIR4733HG	NR_186435.1 link	n.264+161_264+162dupGG	intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.-243_-242dupCC		5_prime_UTR_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000106

AC:

AN:

94174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000221

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

AN:

242174

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

125486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6412

American (AMR)

AF:

0.00

AC:

AN:

8046

Ashkenazi Jewish (ASJ)

AF:

0.000255

AC:

AN:

7842

East Asian (EAS)

AF:

0.00

AC:

AN:

20002

South Asian (SAS)

AF:

0.000719

AC:

AN:

13912

European-Finnish (FIN)

AF:

0.000109

AC:

AN:

18360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1104

European-Non Finnish (NFE)

AF:

0.0000924

AC:

AN:

151588

Other (OTH)

AF:

0.000268

AC:

AN:

14908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000106

AC:

AN:

94178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

45634

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23906

American (AMR)

AF:

0.00

AC:

AN:

8796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2334

East Asian (EAS)

AF:

0.00

AC:

AN:

3692

South Asian (SAS)

AF:

0.00

AC:

AN:

2962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.0000221

AC:

AN:

45162

Other (OTH)

AF:

0.00

AC:

AN:

1240

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.55

Splicing

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

Publications

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NM_001042492.3:c.-243_-242dupCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over