17-31336607-TAA-TA

Variant names:

• chr17-31336607-TA-T
• rs33925668
• NM_001042492.3:c.6148-17delA

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.6148-17delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000865 in 1,456,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.877
• 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 17-31336607-TA-T is Benign according to our data. Variant chr17-31336607-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3037932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 19 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.6148-17delA		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.6085-17delA		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.6148-27delA		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6085-27delA		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1313-27delA		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 19 AN: 149562 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000819 AC: 107 AN: 1306986 Hom.: 0 Cov.: 33 AF XY: 0.0000957 AC XY: 62 AN XY: 647922

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

African (AFR) AF: 0.000396 AC: 11 AN: 27776

American (AMR) AF: 0.0000693 AC: 2 AN: 28846

Ashkenazi Jewish (ASJ) AF: 0.0000856 AC: 2 AN: 23378

East Asian (EAS) AF: 0.000227 AC: 8 AN: 35304

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 73162

European-Finnish (FIN) AF: 0.0000216 AC: 1 AN: 46338

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4570

European-Non Finnish (NFE) AF: 0.0000740 AC: 75 AN: 1013540

Other (OTH) AF: 0.000111 AC: 6 AN: 54072

⚠️ 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: 0.000127 AC: 19 AN: 149648 Hom.: 0 Cov.: 0 AF XY: 0.000110 AC XY: 8 AN XY: 72970

African (AFR) AF: 0.000320 AC: 13 AN: 40640

American (AMR) AF: 0.0000666 AC: 1 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000740 AC: 5 AN: 67546

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 293

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1-related disorder Benign:1

Nov 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
BranchPoint Hunter		5.0
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: rs33925668; hg19: chr17-29663625;