Genetic Variant NM_018353.5:c.2667T>G (chr14-45223920-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018353.5(MIS18BP1):c.2667T>G(p.His889Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MIS18BP1
NM_018353.5 missense, splice_region

Scores

Splicing: ADA: 0.00004542

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0810

Publications

0 publications found

Variant links:

Genes affected

MIS18BP1 (HGNC:20190): (MIS18 binding protein 1) Predicted to enable DNA binding activity. Predicted to be involved in cell division. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MIS18BP1 links:

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ACMG classification

Classification was made for transcript

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=0.32086813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018353.5. 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
	MIS18BP1	NM_018353.5	MANE Select	c.2667T>G	p.His889Gln	missense splice_region	Exon 11 of 17	NP_060823.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIS18BP1	ENST00000310806.9	TSL:1 MANE Select	c.2667T>G	p.His889Gln	missense splice_region	Exon 11 of 17	ENSP00000309790.4	Q6P0N0-1
MIS18BP1	ENST00000919501.1		c.2712T>G	p.His904Gln	missense splice_region	Exon 11 of 17	ENSP00000589560.1
MIS18BP1	ENST00000901126.1		c.2667T>G	p.His889Gln	missense splice_region	Exon 13 of 19	ENSP00000571185.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000938

AC:

AN:

213256

AF XY:

0.00000865

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1413432

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701334

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:

31124

American (AMR)

AF:

0.00

AC:

AN:

34168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23392

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39314

South Asian (SAS)

AF:

0.00

AC:

AN:

78808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093840

Other (OTH)

AF:

0.00

AC:

AN:

58306

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

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

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.041

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.68

M_CAP

Benign

0.013

MetaRNN

Benign

0.32

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

0.081

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.21

Sift

Benign

0.15

Sift4G

Benign

0.22

Polyphen

0.92

Vest4

0.56

MutPred

0.53

Gain of catalytic residue at S894 (P = 0.0207)

MVP

0.30

MPC

0.20

ClinPred

0.70

GERP RS

0.22

Varity_R

0.26

gMVP

0.090

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over