17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTTTTTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001042492.3(NF1):​c.3198-11_3198-4dupTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_3198-4dupTTTTTTTT		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-11_3198-4dupTTTTTTTT		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.3198-30_3198-29insTTTTTTTT		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-30_3198-29insTTTTTTTT		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-30_3198-29insTTTTTTTT		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.0000220 AC: 2 AN: 90908 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000446

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: 0.0000209

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 8 AN: 499014 Hom.: 0 Cov.: 4 AF XY: 0.0000114 AC XY: 3 AN XY: 262428

⚠️ 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: 10162

American (AMR) AF: 0.00 AC: 0 AN: 16036

Ashkenazi Jewish (ASJ) AF: 0.000164 AC: 2 AN: 12226

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 42948

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: 348460

Other (OTH) AF: 0.00 AC: 0 AN: 21848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000812576), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000220 AC: 2 AN: 90908 Hom.: 0 Cov.: 0 AF XY: 0.0000476 AC XY: 2 AN XY: 42040

African (AFR) AF: 0.0000446 AC: 1 AN: 22426

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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;