rs182325576

chr17-31181681-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042492.3(NF1):c.655-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,516,992 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.51

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-31181681-T-C is Benign according to our data. Variant chr17-31181681-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181681-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 355 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.655-29T>C		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.655-29T>C		intron_variant
NF1	NM_001128147.3	c.655-29T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.655-29T>C		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00230 AC: 575 AN: 250418 Hom.: 5 AF XY: 0.00242 AC XY: 328 AN XY: 135532

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00122

Gnomad FIN exome AF: 0.00568

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00265 AC: 3620 AN: 1364700 Hom.: 6 Cov.: 23 AF XY: 0.00269 AC XY: 1844 AN XY: 684428

Gnomad4 AFR exome AF: 0.000565

Gnomad4 AMR exome AF: 0.000965

Gnomad4 ASJ exome AF: 0.00580

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00304

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74488

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00237 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely 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	May 23, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 22, 2019

- -

Neurofibromatosis, familial spinal Benign:1

Likely 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	-0.78
Cadd	Benign	11
Dann	Benign	0.86

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

Other links and lift over

dbSNP: rs182325576; hg19: chr17-29508699; COSMIC: COSV100646144;