NM_001042492.3:c.6148-18_6148-17dupAA

Variant names:

• chr17-31336607-T-TAA
• rs33925668
• NM_001042492.3:c.6148-18_6148-17dupAA

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.6148-18_6148-17dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000895 in 1,453,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00094 (0 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: 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-TAA is Benign according to our data. Variant chr17-31336607-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 928871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000481 (72/149636) while in subpopulation EAS AF = 0.00547 (28/5120). AF 95% confidence interval is 0.00389. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 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.6148-18_6148-17dupAA		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.6085-18_6085-17dupAA		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_6148-27insAA		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6085-28_6085-27insAA		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1313-28_*1313-27insAA		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.000481 AC: 72 AN: 149550 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000533

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00546

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000305

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.00150 AC: 210 AN: 139834 AF XY: 0.00156

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000903

Gnomad EAS exome AF: 0.00571

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.000828

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.000942 AC: 1228 AN: 1303450 Hom.: 0 Cov.: 33 AF XY: 0.000927 AC XY: 599 AN XY: 646184

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

African (AFR) AF: 0.00152 AC: 42 AN: 27560

American (AMR) AF: 0.00153 AC: 44 AN: 28718

Ashkenazi Jewish (ASJ) AF: 0.000685 AC: 16 AN: 23342

East Asian (EAS) AF: 0.00330 AC: 116 AN: 35114

South Asian (SAS) AF: 0.000741 AC: 54 AN: 72894

European-Finnish (FIN) AF: 0.000649 AC: 30 AN: 46234

Middle Eastern (MID) AF: 0.00109 AC: 5 AN: 4570

European-Non Finnish (NFE) AF: 0.000858 AC: 868 AN: 1011070

Other (OTH) AF: 0.000982 AC: 53 AN: 53948

⚠️ 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: 0.000481 AC: 72 AN: 149636 Hom.: 0 Cov.: 0 AF XY: 0.000480 AC XY: 35 AN XY: 72968

African (AFR) AF: 0.000369 AC: 15 AN: 40634

American (AMR) AF: 0.000533 AC: 8 AN: 15022

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

East Asian (EAS) AF: 0.00547 AC: 28 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.000305 AC: 3 AN: 9832

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67544

Other (OTH) AF: 0.00145 AC: 3 AN: 2074

Alfa AF: 0.00104 Hom.: 293

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 02, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.6085-18_6085-17dupAA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 139834 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 600 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6085-18_6085-17dupAA in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

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;