NM_001042492.3:c.6148-19_6148-17dupAAA

Variant names:

• chr17-31336607-T-TAAA
• rs33925668
• NM_001042492.3:c.6148-19_6148-17dupAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001042492.3(NF1):​c.6148-19_6148-17dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,415,564 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0076 (14 hom., cov: 0)
  • Exomes 𝑓: 0.012 (24 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-31336607-T-TAAA is Benign according to our data. Variant chr17-31336607-T-TAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1186284.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00764 (1143/149616) while in subpopulation SAS AF = 0.0109 (52/4752). AF 95% confidence interval is 0.01. There are 14 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1143 AD gene.

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.6148-19_6148-17dupAAA		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.6085-19_6085-17dupAAA		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_6148-27insAAA		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6085-28_6085-27insAAA		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1313-28_*1313-27insAAA		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1135 AN: 149530 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00175

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00520

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.0111

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00876

GnomAD2 exomes AF: 0.0132 AC: 1842 AN: 139834 AF XY: 0.0134

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.00290

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0118 AC: 14896 AN: 1265948 Hom.: 24 Cov.: 33 AF XY: 0.0121 AC XY: 7562 AN XY: 627486

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

African (AFR) AF: 0.00274 AC: 76 AN: 27702

American (AMR) AF: 0.00757 AC: 215 AN: 28394

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 464 AN: 22258

East Asian (EAS) AF: 0.00623 AC: 217 AN: 34854

South Asian (SAS) AF: 0.0131 AC: 923 AN: 70672

European-Finnish (FIN) AF: 0.0182 AC: 822 AN: 45172

Middle Eastern (MID) AF: 0.0149 AC: 66 AN: 4430

European-Non Finnish (NFE) AF: 0.0117 AC: 11490 AN: 980004

Other (OTH) AF: 0.0119 AC: 623 AN: 52462

⚠️ 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: 0.00764 AC: 1143 AN: 149616 Hom.: 14 Cov.: 0 AF XY: 0.00794 AC XY: 579 AN XY: 72956

African (AFR) AF: 0.00202 AC: 82 AN: 40640

American (AMR) AF: 0.00519 AC: 78 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3464

East Asian (EAS) AF: 0.00195 AC: 10 AN: 5120

South Asian (SAS) AF: 0.0109 AC: 52 AN: 4752

European-Finnish (FIN) AF: 0.0135 AC: 133 AN: 9828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0107 AC: 722 AN: 67522

Other (OTH) AF: 0.00868 AC: 18 AN: 2074

Alfa AF: 0.0233 Hom.: 293

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;