chr17-31214419-T-C

Position:

• chr17-31214419-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.1393-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,535,034 control chromosomes in the GnomAD database, including 340,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25785 hom., cov: 31)
  • Exomes 𝑓: 0.67 (314788 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.807

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-31214419-T-C is Benign according to our data. Variant chr17-31214419-T-C is described in ClinVar as [Benign]. Clinvar id is 257276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1393-32T>C		intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1393-32T>C		intron_variant			NP_000258.1
NF1	NM_001128147.3	c.1393-32T>C		intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1393-32T>C		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81601 AN: 151806 Hom.: 25794 Cov.: 31

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.620 AC: 149631 AN: 241458 Hom.: 48749 AF XY: 0.636 AC XY: 83694 AN XY: 131550

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 0.559

Gnomad SAS exome AF: 0.633

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.668

GnomAD4 exome AF: 0.667 AC: 922993 AN: 1383112 Hom.: 314788 Cov.: 23 AF XY: 0.670 AC XY: 463309 AN XY: 691984

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.774

Gnomad4 EAS exome AF: 0.555

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.694

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.537 AC: 81585 AN: 151922 Hom.: 25785 Cov.: 31 AF XY: 0.534 AC XY: 39676 AN XY: 74248

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.625

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.605

Alfa AF: 0.632 Hom.: 5846

Bravo AF: 0.517

Asia WGS AF: 0.565 AC: 1960 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2018	- -

Neurofibromatosis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Neurofibromatosis, familial spinal Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2905876; hg19: chr17-29541437; COSMIC: COSV100645945;