chr17-31336607-T-TAAAA

Variant names:

• chr17-31336607-T-TAAAA
• rs33925668
• NM_001042492.3:c.6148-20_6148-17dupAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001042492.3(NF1):​c.6148-20_6148-17dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,456,670 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.877
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.6148-20_6148-17dupAAAA		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.6085-20_6085-17dupAAAA		intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.6148-28_6148-27insAAAA		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6085-28_6085-27insAAAA		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1313-28_*1313-27insAAAA		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.0000201 AC: 3 AN: 149562 Hom.: 0 Cov.: 0

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: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 19 AN: 139834 AF XY: 0.000145

Gnomad AFR exome AF: 0.000116

Gnomad AMR exome AF: 0.0000562

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000796 AC: 104 AN: 1307108 Hom.: 0 Cov.: 33 AF XY: 0.0000787 AC XY: 51 AN XY: 647996

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

African (AFR) AF: 0.00 AC: 0 AN: 27804

American (AMR) AF: 0.00 AC: 0 AN: 28850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23378

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35316

South Asian (SAS) AF: 0.0000273 AC: 2 AN: 73160

European-Finnish (FIN) AF: 0.000130 AC: 6 AN: 46332

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4572

European-Non Finnish (NFE) AF: 0.0000898 AC: 91 AN: 1013614

Other (OTH) AF: 0.0000555 AC: 3 AN: 54082

⚠️ 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.

GnomAD4 genome AF: 0.0000201 AC: 3 AN: 149562 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72874

African (AFR) AF: 0.00 AC: 0 AN: 40538

American (AMR) AF: 0.00 AC: 0 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67554

Other (OTH) AF: 0.00 AC: 0 AN: 2054

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
BranchPoint Hunter		6.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs33925668; hg19: chr17-29663625;