17-31295887-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002544.5(OMG):c.445G>A(p.Glu149Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,060 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 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: OMG NM_002544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.927

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]

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048725218).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OMG	NM_002544.5	c.445G>A	p.Glu149Lys	missense_variant	2/2	ENST00000247271.5
NF1	NM_001042492.3	c.4836-29933C>T		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.4773-29933C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OMG	ENST00000247271.5	c.445G>A	p.Glu149Lys	missense_variant	2/2	1	NM_002544.5	P1
NF1	ENST00000358273.9	c.4836-29933C>T		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250944 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135608

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74414

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.445G>A (p.E149K) alteration is located in exon 2 (coding exon 1) of the OMG gene. This alteration results from a G to A substitution at nucleotide position 445, causing the glutamic acid (E) at amino acid position 149 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Benign	0.90
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.12
Sift	Benign	0.33	T
Sift4G	Benign	0.99	T
Polyphen		0.0070	B
Vest4		0.095
MVP		0.37
MPC		0.44
ClinPred		0.034	T
GERP RS		3.6
Varity_R		0.094
gMVP		0.49

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: rs182852590; hg19: chr17-29622905; COSMIC: COSV99907894;