17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTTT

Variant names:

• chr17-31232043-ATT-A
• rs371047262
• NM_001042492.3:c.3198-5_3198-4delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.3198-5_3198-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 584,198 control chromosomes in the GnomAD database, including 4 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 0.0085 (3 hom., cov: 0)
  • Exomes 𝑓: 0.010 (1 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.50
• 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 -16 ACMG points.

• BP6: Variant 17-31232043-ATT-A is Benign according to our data. Variant chr17-31232043-ATT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0085 (772/90850) while in subpopulation AFR AF = 0.0321 (720/22408). AF 95% confidence interval is 0.0302. There are 3 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-5_3198-4delTT		splice_region_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3198-5_3198-4delTT		splice_region_variant, intron_variant	Intron 24 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-29_3198-28delTT		intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 768 AN: 90854 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00404

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.000592

Gnomad MID AF: 0.0102

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00738

GnomAD2 exomes AF: 0.00531 AC: 345 AN: 65012 AF XY: 0.00515

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.000457

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.0102 AC: 5041 AN: 493348 Hom.: 1 AF XY: 0.0104 AC XY: 2702 AN XY: 259060

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

African (AFR) AF: 0.0228 AC: 228 AN: 10008

American (AMR) AF: 0.0115 AC: 181 AN: 15794

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 175 AN: 12036

East Asian (EAS) AF: 0.0186 AC: 309 AN: 16570

South Asian (SAS) AF: 0.00794 AC: 335 AN: 42182

European-Finnish (FIN) AF: 0.0102 AC: 292 AN: 28630

Middle Eastern (MID) AF: 0.0199 AC: 33 AN: 1656

European-Non Finnish (NFE) AF: 0.00927 AC: 3197 AN: 344904

Other (OTH) AF: 0.0135 AC: 291 AN: 21568

⚠️ 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: 0.00850 AC: 772 AN: 90850 Hom.: 3 Cov.: 0 AF XY: 0.00900 AC XY: 378 AN XY: 42010

African (AFR) AF: 0.0321 AC: 720 AN: 22408

American (AMR) AF: 0.00404 AC: 30 AN: 7428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.00 AC: 0 AN: 2712

South Asian (SAS) AF: 0.000425 AC: 1 AN: 2352

European-Finnish (FIN) AF: 0.000592 AC: 2 AN: 3380

Middle Eastern (MID) AF: 0.00575 AC: 1 AN: 174

European-Non Finnish (NFE) AF: 0.000188 AC: 9 AN: 47880

Other (OTH) AF: 0.00734 AC: 9 AN: 1226

Alfa AF: 0.000535 Hom.: 224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 30, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1-related disorder Benign:1

Mar 23, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Aug 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs371047262; hg19: chr17-29559061;