Genetic Variant MIS18BP1:p.His934Pro (chr14-45218323-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018353.5(MIS18BP1):c.2801A>C(p.His934Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MIS18BP1
NM_018353.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.188

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03856945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIS18BP1	NM_018353.5 link	c.2801A>C	p.His934Pro	missense_variant	Exon 12 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.2801A>C	p.His934Pro	missense_variant	Exon 12 of 17	1	NM_018353.5	ENSP00000309790.4	Q6P0N0-1
MIS18BP1	ENST00000469020.5 link	n.260A>C		non_coding_transcript_exon_variant	Exon 2 of 4	3
MIS18BP1	ENST00000554093.1 link	n.*82A>C		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000451783.1	H0YJM1
MIS18BP1	ENST00000554093.1 link	n.*82A>C		3_prime_UTR_variant	Exon 2 of 4	3		ENSP00000451783.1	H0YJM1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251312

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2801A>C (p.H934P) alteration is located in exon 12 (coding exon 11) of the MIS18BP1 gene. This alteration results from a A to C substitution at nucleotide position 2801, causing the histidine (H) at amino acid position 934 to be replaced by a proline (P). 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

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.0025

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.48

M_CAP

Benign

0.0033

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.3

REVEL

Benign

0.065

Sift

Benign

0.32

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.16

MVP

0.22

MPC

0.049

ClinPred

0.042

GERP RS

2.8

Varity_R

0.15

gMVP

0.17

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

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