rs1555535403

chr17-31343020-AGTATTTATGGCAATCCGGAATCCTCTG-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM4 PP3 PP5_Moderate

The NM_001042492.3(NF1):c.7076_7102del(p.Val2359_Leu2367del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V2359V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001042492.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-31343020-AGTATTTATGGCAATCCGGAATCCTCTG-A is Pathogenic according to our data. Variant chr17-31343020-AGTATTTATGGCAATCCGGAATCCTCTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 522586.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.7076_7102del	p.Val2359_Leu2367del	inframe_deletion	48/58	ENST00000358273.9
NF1	NM_000267.3	c.7013_7039del	p.Val2338_Leu2346del	inframe_deletion	47/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.7076_7102del	p.Val2359_Leu2367del	inframe_deletion	48/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fan Lab, Zhengzhou University

Jul 12, 2017

The c.7013_7039del mutation in NF1 gene, resulting p.Val2338_Leu2346del in the amino acid sequence of NF1 protein, has not been reported in patient with Neurofibromatosis type 1 yet. According to the functional prediction and two-generation pedigree analysis, this mutation was consider to be pathogenic in our case. -

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: rs1555535403; hg19: chr17-29670038;