Genetic Variant MIS18BP1:p.His889Gln (chr14-45223920-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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. 16/23 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32086813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIS18BP1	NM_018353.5 link	c.2667T>G	p.His889Gln	missense_variant, splice_region_variant	Exon 11 of 17	ENST00000310806.9	NP_060823.3	Q6P0N0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MIS18BP1	ENST00000310806.9 link	c.2667T>G	p.His889Gln	missense_variant, splice_region_variant	Exon 11 of 17	1	NM_018353.5	ENSP00000309790.4	Q6P0N0-1
MIS18BP1	ENST00000469020.5 link	n.126T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	3
MIS18BP1	ENST00000554093.1 link	n.204T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000451783.1	H0YJM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000938

AC:

AN:

213256

Hom.:

AF XY:

0.00000865

AC XY:

AN XY:

115636

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2667T>G (p.H889Q) alteration is located in exon 11 (coding exon 10) of the MIS18BP1 gene. This alteration results from a T to G substitution at nucleotide position 2667, causing the histidine (H) at amino acid position 889 to be replaced by a glutamine (Q). 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

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.24

CADD

Benign

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over