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. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6148-18_6148-17dupAA		intron_variant	Intron 41 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6085-18_6085-17dupAA		intron_variant	Intron 40 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6148-28_6148-27insAA		intron_variant	Intron 41 of 57	1	NM_001042492.3	ENSP00000351015.4

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

GnomAD3 exomes AF: 0.00150 AC: 210 AN: 139834 Hom.: 3 AF XY: 0.00156 AC XY: 118 AN XY: 75790

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 SAS exome AF: 0.000782

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

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.000685

Gnomad4 EAS exome AF: 0.00330

Gnomad4 SAS exome AF: 0.000741

Gnomad4 FIN exome AF: 0.000649

Gnomad4 NFE exome AF: 0.000858

Gnomad4 OTH exome AF: 0.000982

GnomAD4 genome AF: 0.000481 AC: 72 AN: 149636 Hom.: 0 Cov.: 0 AF XY: 0.000480 AC XY: 35 AN XY: 72968

Gnomad4 AFR AF: 0.000369

Gnomad4 AMR AF: 0.000533

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00547

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000305

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00145

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 v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		6.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33925668; hg19: chr17-29663625;