chr17-31232043-ATTTTTTT-A

Position:

• chr17-31232043-ATTTTTTT-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_Strong BS2_Supporting

The NM_001042492.3(NF1):​c.3198-10_3198-4delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 589,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.14

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 17-31232043-ATTTTTTT-A is Benign according to our data. Variant chr17-31232043-ATTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 996498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232043-ATTTTTTT-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 35 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-10_3198-4delTTTTTTT		splice_region_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-10_3198-4delTTTTTTT		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.3198-10_3198-4delTTTTTTT		splice_region_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.000385 AC: 35 AN: 90908 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.00164

GnomAD4 exome AF: 0.000303 AC: 151 AN: 498962 Hom.: 0 AF XY: 0.000286 AC XY: 75 AN XY: 262402

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.000811

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.0000693

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.000412

GnomAD4 genome AF: 0.000385 AC: 35 AN: 90904 Hom.: 0 Cov.: 0 AF XY: 0.000523 AC XY: 22 AN XY: 42042

Gnomad4 AFR AF: 0.000312

Gnomad4 AMR AF: 0.00148

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00128

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000251

Gnomad4 OTH AF: 0.00163

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 26, 2020

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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;