rs786203186

Variant names:

• chr17-31169904-A-G
• rs786203186
• NM_001042492.3:c.493A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-31169904-A-G
• chr17-31169904-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042492.3(NF1):​c.493A>G​(p.Thr165Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.493A>G	p.Thr165Ala	missense_variant	Exon 5 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.493A>G	p.Thr165Ala	missense_variant	Exon 5 of 57		NP_000258.1
NF1	NM_001128147.3	c.493A>G	p.Thr165Ala	missense_variant	Exon 5 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.493A>G	p.Thr165Ala	missense_variant	Exon 5 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457548 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 165 of the NF1 protein (p.Thr165Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 27838393). ClinVar contains an entry for this variant (Variation ID: 186745). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1

Feb 07, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493A>G (p.T165A) alteration is located in exon 5 (coding exon 5) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 493, causing the threonine (T) at amino acid position 165 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 20, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T165A variant (also known as c.493A>G), located in coding exon 5 of the NF1 gene, results from an A to G substitution at nucleotide position 493. The threonine at codon 165 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.<span style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000 alleles tested) in our clinical cohort.<span style="background-color: initial;">This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color: initial;">p.T165A<span style="background-color: initial;">remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	.;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.85	L;L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	.;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.35	.;T;T;T
Sift4G	Benign	0.41	.;T;T;T
Polyphen		0.97	D;B;D;.
Vest4		0.68, 0.61, 0.76
MutPred		0.33		Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);
MVP		0.85
MPC		0.68
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203186; hg19: chr17-29496922;