dbSNP rs17883614: NF1:c.6642+45T>A (chr17-31337627-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042492.3(NF1):c.6642+45T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,555,824 control chromosomes in the GnomAD database, including 5,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 3032 hom., cov: 32)

Exomes 𝑓: 0.024 ( 2942 hom. )

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.98

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 17-31337627-T-A is Benign according to our data. Variant chr17-31337627-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 257297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.6642+45T>A		intron_variant	Intron 43 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.6579+45T>A		intron_variant	Intron 42 of 56		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.6642+45T>A		intron_variant	Intron 43 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18332

AN:

152076

Hom.:

3025

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0559

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.0887

Gnomad SAS

AF:

0.0496

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0986

GnomAD3 exomes

AF:

0.0470

AC:

10963

AN:

233198

Hom.:

1178

AF XY:

0.0428

AC XY:

5449

AN XY:

127256

show subpopulations

Gnomad AFR exome

AF:

0.386

Gnomad AMR exome

AF:

0.0287

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.0848

Gnomad SAS exome

AF:

0.0465

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0243

AC:

34071

AN:

1403630

Hom.:

2942

Cov.:

AF XY:

0.0242

AC XY:

16944

AN XY:

700742

show subpopulations

Gnomad4 AFR exome

AF:

0.389

Gnomad4 AMR exome

AF:

0.0318

Gnomad4 ASJ exome

AF:

0.0180

Gnomad4 EAS exome

AF:

0.0987

Gnomad4 SAS exome

AF:

0.0470

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.00844

Gnomad4 OTH exome

AF:

0.0417

GnomAD4 genome

AF:

0.121

AC:

18355

AN:

152194

Hom.:

3032

Cov.:

AF XY:

0.119

AC XY:

8866

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.374

Gnomad4 AMR

AF:

0.0558

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.0878

Gnomad4 SAS

AF:

0.0495

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.0975

Alfa

AF:

0.0618

Hom.:

240

Bravo

AF:

0.135

Asia WGS

AF:

0.0800

AC:

279

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, familial spinal

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.11

DANN

Benign

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over