chr17-31232043-ATTTT-A

Position:

• chr17-31232043-ATTTT-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001042492.3(NF1):​c.3198-7_3198-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 589,162 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000044 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-7_3198-4delTTTT		splice_region_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-7_3198-4delTTTT		splice_region_variant, intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-7_3198-4delTTTT		splice_region_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.0000440 AC: 4 AN: 90908 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000178

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000622 AC: 310 AN: 498258 Hom.: 0 AF XY: 0.000660 AC XY: 173 AN XY: 262012

Gnomad4 AFR exome AF: 0.00533

Gnomad4 AMR exome AF: 0.000751

Gnomad4 ASJ exome AF: 0.000984

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.000350

Gnomad4 FIN exome AF: 0.000625

Gnomad4 NFE exome AF: 0.000468

Gnomad4 OTH exome AF: 0.000826

GnomAD4 genome AF: 0.0000440 AC: 4 AN: 90904 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42042

Gnomad4 AFR AF: 0.000178

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs371047262; hg19: chr17-29559061;