17-31232043-ATTTTTTTTTTTTTTT-ATTTTTT

Variant names:

• chr17-31232043-ATTTTTTTTT-A
• rs371047262
• NM_001042492.3:c.3198-12_3198-4delTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP6_Moderate BS2_Supporting

The NM_001042492.3(NF1):​c.3198-12_3198-4delTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 589,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.14
• 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: Likely_benign. The variant received -3 ACMG points.

• BP6: Variant 17-31232043-ATTTTTTTTT-A is Benign according to our data. Variant chr17-31232043-ATTTTTTTTT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3341696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 20 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3198-12_3198-4delTTTTTTTTT		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-12_3198-4delTTTTTTTTT		splice_region 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.3198-29_3198-21delTTTTTTTTT		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-29_3198-21delTTTTTTTTT		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-29_3198-21delTTTTTTTTT		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.000220 AC: 20 AN: 90908 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000209

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000802 AC: 40 AN: 499006 Hom.: 0 AF XY: 0.0000648 AC XY: 17 AN XY: 262424

African (AFR) AF: 0.00177 AC: 18 AN: 10160

American (AMR) AF: 0.0000624 AC: 1 AN: 16036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12226

East Asian (EAS) AF: 0.000119 AC: 2 AN: 16806

South Asian (SAS) AF: 0.000210 AC: 9 AN: 42946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1682

European-Non Finnish (NFE) AF: 0.0000172 AC: 6 AN: 348456

Other (OTH) AF: 0.000183 AC: 4 AN: 21848

GnomAD4 genome AF: 0.000220 AC: 20 AN: 90908 Hom.: 0 Cov.: 0 AF XY: 0.000214 AC XY: 9 AN XY: 42040

African (AFR) AF: 0.000713 AC: 16 AN: 22426

American (AMR) AF: 0.000269 AC: 2 AN: 7422

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2728

South Asian (SAS) AF: 0.000424 AC: 1 AN: 2360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.0000209 AC: 1 AN: 47886

Other (OTH) AF: 0.00 AC: 0 AN: 1220

Alfa AF: 0.00 Hom.: 224

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: BP4, BS1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
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: rs371047262; hg19: chr17-29559061;