rs199641099

Positions:

• chr17-31356628-G-A
• chr17-31356628-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.7738+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,609,164 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (81 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0580

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=-0.79).
• BP6: Variant 17-31356628-G-A is Benign according to our data. Variant chr17-31356628-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00457 (695/152170) while in subpopulation SAS AF= 0.0149 (72/4828). AF 95% confidence interval is 0.0121. There are 2 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 695 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7738+46G>A		intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7675+46G>A		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7738+46G>A		intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00661 AC: 1639 AN: 247902 Hom.: 21 AF XY: 0.00772 AC XY: 1035 AN XY: 133986

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.00635

Gnomad NFE exome AF: 0.00664

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00746 AC: 10870 AN: 1456994 Hom.: 81 Cov.: 30 AF XY: 0.00801 AC XY: 5809 AN XY: 724798

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00688

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00627

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74432

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00632

Gnomad4 NFE AF: 0.00645

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00524 Hom.: 1

Bravo AF: 0.00400

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

NF1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199641099; hg19: chr17-29683646; COSMIC: COSV104420563; COSMIC: COSV104420563;