17-31349086-CTTGTTTGTTTGTTTGT-CTTGTTTGTTTGT

Variant names:

• chr17-31349086-CTTGT-C
• rs149197458
• NM_001042492.3:c.7190-11_7190-8delGTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.7190-11_7190-8delGTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0057 in 1,541,198 control chromosomes in the GnomAD database, including 318 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (165 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (153 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.75

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 -16 ACMG points.

• BP6: Variant 17-31349086-CTTGT-C is Benign according to our data. Variant chr17-31349086-CTTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 226852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31349086-CTTGT-C is described in Lovd as [Benign]. Variant chr17-31349086-CTTGT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7190-11_7190-8delGTTT		splice_region_variant, intron_variant	Intron 48 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7127-11_7127-8delGTTT		splice_region_variant, intron_variant	Intron 47 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7190-33_7190-30delTTGT		intron_variant	Intron 48 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3856 AN: 151948 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.00818 AC: 1265 AN: 154686 Hom.: 44 AF XY: 0.00635 AC XY: 519 AN XY: 81712

Gnomad AFR exome AF: 0.0942

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.000360

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00355 AC: 4927 AN: 1389136 Hom.: 153 AF XY: 0.00310 AC XY: 2128 AN XY: 686016

Gnomad4 AFR exome AF: 0.0935

Gnomad4 AMR exome AF: 0.00856

Gnomad4 ASJ exome AF: 0.000481

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00138

Gnomad4 NFE exome AF: 0.000967

Gnomad4 OTH exome AF: 0.00741

GnomAD4 genome AF: 0.0254 AC: 3860 AN: 152062 Hom.: 165 Cov.: 32 AF XY: 0.0238 AC XY: 1766 AN XY: 74336

Gnomad4 AFR AF: 0.0859

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0194

Bravo AF: 0.0301

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Oct 26, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.7190-11_7190-8delGTTT (HGVS nomenclature: c.7190-31_7190-28[5]) in intron 48 o f NF1: This variant is not expected to have clinical significance because it has been identified in 10.6% (312/2980) of African chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; rs149197458). This varian t is not predicted to impact splicing. -

Jul 01, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 16, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NF1 c.7127-11_7127-8delGTTT variant involves the deletion of four intronic nucleotides in a six (GTTT) repeat region. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant, listed as 17:29676104 CTTGT / Cin the ExAC control database, was found in 444/23188 control chromosomes (19 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.104698 (312/2980). This frequency is about 502 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, the variant is classified as benign. -

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Jul 08, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome Benign:1

Jun 12, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs149197458; hg19: chr17-29676104;