17-31326019-A-G

Variant names:

• chr17-31326019-A-G
• rs147327414
• NM_001042492.3:c.5035A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.5035A>G​(p.Ile1679Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,152 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1679M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (37 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 1.61
• Publications: 8 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 -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 22 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007952929).
• BP6: Variant 17-31326019-A-G is Benign according to our data. Variant chr17-31326019-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00208 (316/152266) while in subpopulation AMR AF = 0.0188 (287/15296). AF 95% confidence interval is 0.017. There are 4 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 316 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.5035A>G	p.Ile1679Val	missense	Exon 37 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.4972A>G	p.Ile1658Val	missense	Exon 36 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.5035A>G	p.Ile1679Val	missense	Exon 37 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.4972A>G	p.Ile1658Val	missense	Exon 36 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.*200A>G		non_coding_transcript_exon	Exon 37 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152148 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00492 AC: 1236 AN: 251434 AF XY: 0.00379

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1461886 Hom.: 37 Cov.: 32 AF XY: 0.000921 AC XY: 670 AN XY: 727240

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.0328 AC: 1468 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112004

Other (OTH) AF: 0.00111 AC: 67 AN: 60396

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152266 Hom.: 4 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74444

African (AFR) AF: 0.000433 AC: 18 AN: 41544

American (AMR) AF: 0.0188 AC: 287 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000542 Hom.: 1

Bravo AF: 0.00380

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00370 AC: 449

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Neurofibromatosis, type 1 (5)
-	1	4	not provided (5)
-	-	4	not specified (5)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Hereditary cancer-predisposing syndrome (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	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.9
DANN	Benign	0.89
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.074
Sift	Benign	0.16	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.44
MPC		0.58
ClinPred		0.0041	T
GERP RS		0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.38
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs147327414; hg19: chr17-29653037; COSMIC: COSV99907657;