rs112306990

Variant names:

• chr17-31169939-T-A
• rs112306990
• NM_001042492.3:c.528T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31169939-T-A
• chr17-31169939-T-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001042492.3(NF1):​c.528T>A​(p.Asp176Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,612,888 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (12 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:26 O:1
• Conservation: PhyloP100: 2.08
• Publications: 44 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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 38 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010571599).
• BP6: Variant 17-31169939-T-A is Benign according to our data. Variant chr17-31169939-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41673.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00375 (571/152322) while in subpopulation NFE AF = 0.00542 (369/68034). AF 95% confidence interval is 0.00497. There are 5 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 571 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.528T>A	p.Asp176Glu	missense	Exon 5 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.528T>A	p.Asp176Glu	missense	Exon 5 of 57	NP_000258.1
	NF1	NM_001128147.3		c.528T>A	p.Asp176Glu	missense	Exon 5 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.528T>A	p.Asp176Glu	missense	Exon 5 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.528T>A	p.Asp176Glu	missense	Exon 5 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.528T>A	p.Asp176Glu	missense	Exon 5 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 571 AN: 152204 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00348 AC: 873 AN: 251164 AF XY: 0.00359

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00416 AC: 6074 AN: 1460566 Hom.: 12 Cov.: 30 AF XY: 0.00407 AC XY: 2954 AN XY: 726612

African (AFR) AF: 0.000598 AC: 20 AN: 33450

American (AMR) AF: 0.00107 AC: 48 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26108

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39582

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86234

European-Finnish (FIN) AF: 0.0102 AC: 543 AN: 53316

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00469 AC: 5209 AN: 1111114

Other (OTH) AF: 0.00360 AC: 217 AN: 60332

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152322 Hom.: 5 Cov.: 32 AF XY: 0.00369 AC XY: 275 AN XY: 74484

African (AFR) AF: 0.000914 AC: 38 AN: 41562

American (AMR) AF: 0.00196 AC: 30 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00542 AC: 369 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00448 Hom.: 1

Bravo AF: 0.00292

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	7	not provided (7)
-	1	4	Neurofibromatosis, type 1 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Neurofibromatosis-Noonan syndrome (1)
-	-	1	Neurofibromatosis, familial spinal (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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	0.092
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.64
Sift	Benign	0.24	T
Sift4G	Benign	0.11	T
Polyphen		0.40	B
Vest4		0.75
MutPred		0.79		Gain of helix (P = 0.062)
MVP		0.86
MPC		0.72
ClinPred		0.020	T
GERP RS		3.4
Varity_R		0.20
gMVP		0.54
Mutation Taster		=80/20	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: rs112306990; hg19: chr17-29496957; COSMIC: COSV62191719;