17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTTTT

Variant names:

• chr17-31232043-AT-A
• rs371047262
• NM_001042492.3:c.3198-4delT

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.3198-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (9 hom., cov: 0)
  • Exomes 𝑓: 0.044 (2 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: 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-AT-A is Benign according to our data. Variant chr17-31232043-AT-A is described in ClinVar as Benign. ClinVar VariationId is 996534.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 = 0.0147 (1336/90874) while in subpopulation AFR AF = 0.0325 (730/22436). AF 95% confidence interval is 0.0306. There are 9 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1336 AD gene.

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

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1335 AN: 90878 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.0118

Gnomad AMR AF: 0.00971

Gnomad ASJ AF: 0.00919

Gnomad EAS AF: 0.00220

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.00473

Gnomad MID AF: 0.0204

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.0164

GnomAD2 exomes AF: 0.0294 AC: 1910 AN: 65012 AF XY: 0.0276

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.0617

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.0310

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0442 AC: 21769 AN: 492098 Hom.: 2 Cov.: 4 AF XY: 0.0471 AC XY: 12169 AN XY: 258232

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

African (AFR) AF: 0.0464 AC: 465 AN: 10026

American (AMR) AF: 0.0486 AC: 765 AN: 15750

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 679 AN: 12078

East Asian (EAS) AF: 0.0743 AC: 1229 AN: 16538

South Asian (SAS) AF: 0.0418 AC: 1743 AN: 41714

European-Finnish (FIN) AF: 0.0387 AC: 1106 AN: 28602

Middle Eastern (MID) AF: 0.0636 AC: 105 AN: 1652

European-Non Finnish (NFE) AF: 0.0421 AC: 14506 AN: 344164

Other (OTH) AF: 0.0543 AC: 1171 AN: 21574

⚠️ 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: 0.0147 AC: 1336 AN: 90874 Hom.: 9 Cov.: 0 AF XY: 0.0158 AC XY: 664 AN XY: 42024

African (AFR) AF: 0.0325 AC: 730 AN: 22436

American (AMR) AF: 0.00970 AC: 72 AN: 7426

Ashkenazi Jewish (ASJ) AF: 0.00919 AC: 24 AN: 2612

East Asian (EAS) AF: 0.00221 AC: 6 AN: 2712

South Asian (SAS) AF: 0.0318 AC: 75 AN: 2356

European-Finnish (FIN) AF: 0.00473 AC: 16 AN: 3380

Middle Eastern (MID) AF: 0.0172 AC: 3 AN: 174

European-Non Finnish (NFE) AF: 0.00798 AC: 382 AN: 47874

Other (OTH) AF: 0.0163 AC: 20 AN: 1226

Alfa AF: 0.00500 Hom.: 224

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 09, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neurofibromatosis, type 1 Benign:2

Mar 15, 2022

Genome-Nilou Lab

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

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;