Genetic Variant NM_138983.3:c.623T>C (chr21-33070869-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138983.3(OLIG1):c.623T>C(p.Val208Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000785 in 1,274,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

OLIG1
NM_138983.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0740

Publications

0 publications found

Variant links:

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]

OLIG1 links:

ENSG00000227757 (HGNC:):

ENSG00000227757 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16355276).

BS2

High AC in GnomAd4 at 9 AD gene.

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.623T>C	p.Val208Ala	missense	Exon 1 of 1	NP_620450.2	Q8TAK6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OLIG1	ENST00000382348.2	TSL:6 MANE Select	c.623T>C	p.Val208Ala	missense	Exon 1 of 1	ENSP00000371785.1	Q8TAK6
ENSG00000227757	ENST00000454622.2	TSL:2	n.201+35A>G		intron	N/A
ENSG00000227757	ENST00000777421.1		n.91+35A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000599

AC:

AN:

150286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.90e-7

AC:

AN:

1124094

Hom.:

Cov.:

AF XY:

0.00000185

AC XY:

AN XY:

540012

show subpopulations

African (AFR)

AF:

0.0000444

AC:

AN:

22506

American (AMR)

AF:

0.00

AC:

AN:

8140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14478

East Asian (EAS)

AF:

0.00

AC:

AN:

25278

South Asian (SAS)

AF:

0.00

AC:

AN:

37296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2984

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

943614

Other (OTH)

AF:

0.00

AC:

AN:

44778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000599

AC:

AN:

150286

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73382

show subpopulations

African (AFR)

AF:

0.000219

AC:

AN:

41156

American (AMR)

AF:

0.00

AC:

AN:

15098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67562

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000604

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.34

PhyloP100

0.074

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.010

REVEL

Benign

0.18

Sift

Uncertain

0.015

Sift4G

Benign

0.70

Polyphen

0.0010

Vest4

0.044

MutPred

0.30

Gain of relative solvent accessibility (P = 0.0023)

MVP

0.57

MPC

1.7

ClinPred

0.087

GERP RS

2.3

PromoterAI

0.049

Neutral

(source)

Varity_R

0.095

gMVP

0.28

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over