17-31296181-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002544.5(OMG):c.151T>C(p.Ser51Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

OMG
NM_002544.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56

Variant links:

Genes affected

OMG (HGNC:8135): (oligodendrocyte myelin glycoprotein) Predicted to enable identical protein binding activity. Predicted to be involved in neuron projection regeneration. Predicted to act upstream of or within regulation of collateral sprouting of intact axon in response to injury. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

OMG links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06413451).

BS2

High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
OMG	NM_002544.5 linkuse as main transcript	c.151T>C	p.Ser51Pro	missense_variant	2/2	ENST00000247271.5
NF1	NM_001042492.3 linkuse as main transcript	c.4836-29639A>G		intron_variant		ENST00000358273.9
NF1	NM_000267.3 linkuse as main transcript	c.4773-29639A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OMG	ENST00000247271.5 linkuse as main transcript	c.151T>C	p.Ser51Pro	missense_variant	2/2	1	NM_002544.5	P1
NF1	ENST00000358273.9 linkuse as main transcript	c.4836-29639A>G		intron_variant		1	NM_001042492.3	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250884

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461130

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 01, 2023

Variant summary: NF1 c.4773-29639A>G is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant also affects another gene, embedded within intron 35 of the NF1 gene (NM_000267.3), resulting in a missense change, i.e. OMG c.151T>C (p.Ser51Pro). The variant allele was found at a frequency of 2.8e-05 in 250884 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4773-29639A>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.70

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Benign

0.41

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.61

M_CAP

Benign

0.0028

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.015

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.57

REVEL

Benign

0.074

Sift

Benign

0.32

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.090

MutPred

0.46

Gain of catalytic residue at P50 (P = 0.0179);

MVP

0.24

MPC

0.48

ClinPred

0.062

GERP RS

2.8

Varity_R

0.14

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over