rs1555614832

Variant names:

• chr17-31232113-C-A
• rs1555614832
• NM_001042492.3:c.3238C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31232113-C-A
• chr17-31232113-C-G
• chr17-31232113-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001042492.3(NF1):​c.3238C>A​(p.Leu1080Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1080P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 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: Likely_pathogenic. The variant received 6 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, 13 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31232114-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3238C>A	p.Leu1080Ile	missense_variant	Exon 25 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3238C>A	p.Leu1080Ile	missense_variant	Exon 25 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3238C>A	p.Leu1080Ile	missense_variant	Exon 25 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.11e-7 AC: 1 AN: 1232568 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 616166

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27974

American (AMR) AF: 0.00 AC: 0 AN: 40690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21184

East Asian (EAS) AF: 0.00 AC: 0 AN: 28878

South Asian (SAS) AF: 0.00 AC: 0 AN: 81818

European-Finnish (FIN) AF: 0.0000231 AC: 1 AN: 43362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 935730

Other (OTH) AF: 0.00 AC: 0 AN: 48824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	M;M;.
PhyloP100		2.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.66
MutPred		0.43		Gain of catalytic residue at L1085 (P = 0.1037);Gain of catalytic residue at L1085 (P = 0.1037);.;
MVP		0.49
MPC		1.7
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.39
Mutation Taster		=37/63	disease causing

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: rs1555614832; hg19: chr17-29559131;