NM_001042492.3:c.7189+37C>G

Variant names:

• chr17-31343172-C-G
• rs7405740
• NM_001042492.3:c.7189+37C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.7189+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,544,818 control chromosomes in the GnomAD database, including 644,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59692 hom., cov: 32)
  • Exomes 𝑓: 0.92 (584630 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.43
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-31343172-C-G is Benign according to our data. Variant chr17-31343172-C-G is described in ClinVar as Benign. ClinVar VariationId is 257300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.7189+37C>G		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.7126+37C>G		intron	N/A	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.7189+37C>G		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.7126+37C>G		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*2354+37C>G		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134465 AN: 152130 Hom.: 59658 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.907 AC: 221128 AN: 243688 AF XY: 0.912

Gnomad AFR exome AF: 0.799

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.881

Gnomad FIN exome AF: 0.944

Gnomad NFE exome AF: 0.915

Gnomad OTH exome AF: 0.901

GnomAD4 exome AF: 0.916 AC: 1275297 AN: 1392570 Hom.: 584630 Cov.: 22 AF XY: 0.917 AC XY: 639141 AN XY: 696714

African (AFR) AF: 0.795 AC: 25486 AN: 32044

American (AMR) AF: 0.886 AC: 39333 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 23550 AN: 25664

East Asian (EAS) AF: 0.925 AC: 36372 AN: 39338

South Asian (SAS) AF: 0.949 AC: 80315 AN: 84616

European-Finnish (FIN) AF: 0.945 AC: 48564 AN: 51388

Middle Eastern (MID) AF: 0.869 AC: 4873 AN: 5610

European-Non Finnish (NFE) AF: 0.917 AC: 964456 AN: 1051442

Other (OTH) AF: 0.901 AC: 52348 AN: 58068

GnomAD4 genome AF: 0.884 AC: 134554 AN: 152248 Hom.: 59692 Cov.: 32 AF XY: 0.888 AC XY: 66078 AN XY: 74450

African (AFR) AF: 0.801 AC: 33234 AN: 41516

American (AMR) AF: 0.877 AC: 13419 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3190 AN: 3472

East Asian (EAS) AF: 0.891 AC: 4615 AN: 5180

South Asian (SAS) AF: 0.952 AC: 4599 AN: 4830

European-Finnish (FIN) AF: 0.950 AC: 10084 AN: 10614

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.918 AC: 62472 AN: 68024

Other (OTH) AF: 0.867 AC: 1832 AN: 2112

Alfa AF: 0.902 Hom.: 11384

Bravo AF: 0.872

Asia WGS AF: 0.898 AC: 3120 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neurofibromatosis, type 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Neurofibromatosis, familial spinal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.69
PhyloP100		-1.4
PromoterAI		0.0025	Neutral
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs7405740; hg19: chr17-29670190;