17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTT

Variant names:

• chr17-31232043-ATTTTTTTT-A
• rs371047262
• NM_001042492.3:c.3198-11_3198-4delTTTTTTTT

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.3198-11_3198-4delTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 589,902 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-31232043-ATTTTTTTT-A is Benign according to our data. Variant chr17-31232043-ATTTTTTTT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 996465.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 = 0.00449 (408/90910) while in subpopulation AFR AF = 0.0171 (383/22462). AF 95% confidence interval is 0.0156. There are 6 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 408 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.3198-11_3198-4delTTTTTTTT		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-11_3198-4delTTTTTTTT		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_3198-22delTTTTTTTT		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-29_3198-22delTTTTTTTT		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-29_3198-22delTTTTTTTT		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 404 AN: 90914 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

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: 0.0000209

Gnomad OTH AF: 0.00410

GnomAD4 exome AF: 0.000435 AC: 217 AN: 498992 Hom.: 0 AF XY: 0.000393 AC XY: 103 AN XY: 262418

African (AFR) AF: 0.0156 AC: 158 AN: 10156

American (AMR) AF: 0.000873 AC: 14 AN: 16028

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 16806

South Asian (SAS) AF: 0.0000699 AC: 3 AN: 42948

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

Middle Eastern (MID) AF: 0.00119 AC: 2 AN: 1682

European-Non Finnish (NFE) AF: 0.0000517 AC: 18 AN: 348454

Other (OTH) AF: 0.00101 AC: 22 AN: 21846

GnomAD4 genome AF: 0.00449 AC: 408 AN: 90910 Hom.: 6 Cov.: 0 AF XY: 0.00466 AC XY: 196 AN XY: 42044

African (AFR) AF: 0.0171 AC: 383 AN: 22462

American (AMR) AF: 0.00256 AC: 19 AN: 7434

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2352

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.0000209 AC: 1 AN: 47880

Other (OTH) AF: 0.00408 AC: 5 AN: 1226

Alfa AF: 0.00 Hom.: 224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:2

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;