NM_001042492.3:c.1042T>C

Variant names:

• chr17-31200575-T-C
• rs864622064
• NM_001042492.3:c.1042T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_001042492.3(NF1):​c.1042T>C​(p.Ser348Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.37

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 2 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.
• BP6: Variant 17-31200575-T-C is Benign according to our data. Variant chr17-31200575-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219385.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1042T>C	p.Ser348Pro	missense_variant	Exon 9 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1042T>C	p.Ser348Pro	missense_variant	Exon 9 of 57		NP_000258.1
NF1	NM_001128147.3	c.1042T>C	p.Ser348Pro	missense_variant	Exon 9 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1042T>C	p.Ser348Pro	missense_variant	Exon 9 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S348P variant (also known as c.1042T>C), located in coding exon 9 of the NF1 gene, results from a T to C substitution at nucleotide position 1042. The serine at codon 348 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Neurofibromatosis, type 1 Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;.;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;D;T;T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	.;D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.094	.;T;T;T;T
Sift4G	Benign	0.12	.;T;T;T;T
Polyphen		0.0040	B;B;D;.;.
Vest4		0.89, 0.90, 0.96
MutPred		0.48		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);.;
MVP		0.78
MPC		0.87
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.84

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: rs864622064; hg19: chr17-29527593;