chr6-137494030-C-T

Variant names:

• chr6-137494030-C-T
• rs879149209
• NM_175747.2:c.141G>A

Variant summary

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

The NM_175747.2(OLIG3):​c.141G>A​(p.Met47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,590 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M47V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: OLIG3 NM_175747.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.915

Genes affected

OLIG3 (HGNC:18003): (oligodendrocyte transcription factor 3) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in neuron differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II; spinal cord motor neuron cell fate specification; and spinal cord motor neuron migration. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056990385).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLIG3	NM_175747.2	c.141G>A	p.Met47Ile	missense_variant	Exon 1 of 1	ENST00000367734.4	NP_786923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OLIG3	ENST00000367734.4	c.141G>A	p.Met47Ile	missense_variant	Exon 1 of 1	6	NM_175747.2	ENSP00000356708.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248482 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134648

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460590 Hom.: 1 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726674

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000472 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.141G>A (p.M47I) alteration is located in exon 1 (coding exon 1) of the OLIG3 gene. This alteration results from a G to A substitution at nucleotide position 141, causing the methionine (M) at amino acid position 47 to be replaced by an isoleucine (I). 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	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.33
Sift	Benign	0.37	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.22		Gain of catalytic residue at M47 (P = 0.019);
MVP		0.10
MPC		0.75
ClinPred		0.12	T
GERP RS		4.7
Varity_R		0.26
gMVP		0.20

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: rs879149209; hg19: chr6-137815167;