rs17881168

Variant names:

• chr17-31156090-C-T
• rs17881168
• NM_001042492.3:c.168C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-31156090-C-T
• chr17-31156090-C-A
• chr17-31156090-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001042492.3(NF1):​c.168C>T​(p.Ser56Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,613,212 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.020 (311 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -0.416
• Publications: 16 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-31156090-C-T is Benign according to our data. Variant chr17-31156090-C-T is described in ClinVar as Benign. ClinVar VariationId is 184126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.416 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2004/151898) while in subpopulation NFE AF = 0.0232 (1576/67962). AF 95% confidence interval is 0.0222. There are 17 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2004 AD gene.

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.168C>T	p.Ser56Ser	synonymous	Exon 2 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 57	NP_000258.1
	NF1	NM_001128147.3		c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 15	NP_001121619.1	P21359-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2003 AN: 151780 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00424

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00643

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00478

Gnomad FIN AF: 0.00832

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.0120 AC: 3002 AN: 251200 AF XY: 0.0119

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0198 AC: 28900 AN: 1461314 Hom.: 311 Cov.: 33 AF XY: 0.0193 AC XY: 14003 AN XY: 726964

African (AFR) AF: 0.00308 AC: 103 AN: 33460

American (AMR) AF: 0.00601 AC: 269 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 181 AN: 26122

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39604

South Asian (SAS) AF: 0.00554 AC: 478 AN: 86240

European-Finnish (FIN) AF: 0.0106 AC: 564 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0237 AC: 26290 AN: 1111618

Other (OTH) AF: 0.0165 AC: 999 AN: 60372

GnomAD4 genome AF: 0.0132 AC: 2004 AN: 151898 Hom.: 17 Cov.: 32 AF XY: 0.0120 AC XY: 888 AN XY: 74212

African (AFR) AF: 0.00422 AC: 175 AN: 41438

American (AMR) AF: 0.00642 AC: 98 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4810

European-Finnish (FIN) AF: 0.00832 AC: 87 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1576 AN: 67962

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0185 Hom.: 17

Bravo AF: 0.0127

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0216

EpiControl AF: 0.0172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Neurofibromatosis, type 1 (5)
-	-	4	not provided (4)
-	-	2	Neurofibromatosis, familial spinal (2)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	-	1	Neurofibromatosis-Noonan syndrome (1)
-	-	1	Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.9
DANN	Benign	0.70
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

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: rs17881168; hg19: chr17-29483108; COSMIC: COSV62213488;