17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTTT

Position:

• chr17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 220515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232043-ATT-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-5_3198-4delTT		splice_region_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-5_3198-4delTT		splice_region_variant, intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-5_3198-4delTT		splice_region_variant, intron_variant		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

GnomAD3 exomes AF: 0.00531 AC: 345 AN: 65012 Hom.: 0 AF XY: 0.00515 AC XY: 180 AN XY: 34954

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 SAS exome AF: 0.00497

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

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.00794

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00927

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.00850 AC: 772 AN: 90850 Hom.: 3 Cov.: 0 AF XY: 0.00900 AC XY: 378 AN XY: 42010

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00404

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000425

Gnomad4 FIN AF: 0.000592

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00734

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2016	- -

NF1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2019

- -

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: rs371047262; hg19: chr17-29559061;