Genetic Variant NM_001393704.1:c.190G>C (chr3-39502259-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393704.1(MOBP):c.190G>C(p.Ala64Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A64T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MOBP
NM_001393704.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Publications

0 publications found

Variant links:

Genes affected

MOBP (HGNC:7189): (myelin associated oligodendrocyte basic protein) Predicted to enable actin binding activity and myosin binding activity. Predicted to be a structural constituent of myelin sheath. Predicted to be involved in nervous system development. Predicted to be located in mitochondrion. Predicted to be active in cortical actin cytoskeleton. Implicated in frontotemporal dementia. [provided by Alliance of Genome Resources, Apr 2022]

MOBP links:

ENSG00000285885 (HGNC:):

ENSG00000285885 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOBP	NM_001393704.1 link	c.190G>C	p.Ala64Pro	missense_variant	Exon 3 of 4	ENST00000684792.1	NP_001380633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOBP	ENST00000684792.1 link	c.190G>C	p.Ala64Pro	missense_variant	Exon 3 of 4		NM_001393704.1	ENSP00000508923.1		Q13875-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250544

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000576

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T;.;.;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;.;.;.;.;.;T

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.74

N;N;N;N;N;N;N

PhyloP100

6.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.1

N;D;N;N;N;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.013

D;D;D;D;D;D;D

Sift4G

Uncertain

0.042

D;D;D;D;D;D;T

Polyphen

1.0

D;D;D;D;D;D;.

Vest4

0.63

MutPred

0.58

Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);Gain of glycosylation at A64 (P = 0.0117);

MVP

0.79

MPC

1.6

ClinPred

0.45

GERP RS

3.9

Varity_R

0.69

gMVP

0.69

Mutation Taster

=68/32

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over