21-33070937-C-A

Variant names:

• chr21-33070937-C-A
• NM_138983.3:c.691C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138983.3(OLIG1):​c.691C>A​(p.Gln231Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. Q231P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: OLIG1 NM_138983.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00
• Publications: 0 publications found

Genes affected

OLIG1 (HGNC:16983): (oligodendrocyte transcription factor 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific 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 neuron fate commitment. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000227757 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36629552).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138983.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OLIG1	NM_138983.3	MANE Select	c.691C>A	p.Gln231Lys	missense	Exon 1 of 1	NP_620450.2	Q8TAK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OLIG1	ENST00000382348.2	TSL:6 MANE Select	c.691C>A	p.Gln231Lys	missense	Exon 1 of 1	ENSP00000371785.1	Q8TAK6
	ENSG00000227757	ENST00000454622.2	TSL:2	n.168G>T		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000227757	ENST00000777421.1		n.58G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303564 Hom.: 0 Cov.: 32 AF XY: 0.00000156 AC XY: 1 AN XY: 642268

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25980

American (AMR) AF: 0.00 AC: 0 AN: 23354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22398

East Asian (EAS) AF: 0.00 AC: 0 AN: 27882

South Asian (SAS) AF: 0.00 AC: 0 AN: 70786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 9.59e-7 AC: 1 AN: 1042990

Other (OTH) AF: 0.00 AC: 0 AN: 53910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.34	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.015	D
Sift4G	Benign	0.50	T
Polyphen		0.47	P
Vest4		0.31
MutPred		0.37		Gain of methylation at Q231 (P = 0.0054)
MVP		0.86
MPC		2.0
ClinPred		0.27	T
GERP RS		4.7
PromoterAI		0.080	Neutral
Varity_R		0.35
gMVP		0.46
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr21-34443243;