rs1227046003

Variant names:

• chr17-31232067-T-TTTC
• rs1227046003
• NM_001042492.3:c.3198-5_3198-3dupTTC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PVS1_Moderate PM2 BP6_Moderate

The NM_001042492.3(NF1):​c.3198-5_3198-3dupTTC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 148,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.305
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013732394 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: ttttttttttttttcttcAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-31232067-T-TTTC is Benign according to our data. Variant chr17-31232067-T-TTTC is described in ClinVar as [Likely_benign]. Clinvar id is 404508.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-5_3198-3dupTTC		splice_acceptor_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3198-5_3198-3dupTTC		splice_acceptor_variant, intron_variant	Intron 24 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-6_3198-5insTTC		splice_region_variant, intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148238 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.89e-7 AC: 1 AN: 1266972 Hom.: 0 Cov.: 20 AF XY: 0.00000159 AC XY: 1 AN XY: 629756

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

African (AFR) AF: 0.00 AC: 0 AN: 26980

American (AMR) AF: 0.00 AC: 0 AN: 29602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23404

East Asian (EAS) AF: 0.00 AC: 0 AN: 36112

South Asian (SAS) AF: 0.00 AC: 0 AN: 69996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3688

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 976022

Other (OTH) AF: 0.00 AC: 0 AN: 52664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148238 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 1 AN XY: 72346

African (AFR) AF: 0.00 AC: 0 AN: 39464

American (AMR) AF: 0.00 AC: 0 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67320

Other (OTH) AF: 0.00 AC: 0 AN: 1986

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Benign:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1227046003; hg19: chr17-29559085;