Genetic Variant NM_018944.3:c.13C>T (chr21-32279002-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018944.3(MIS18A):c.13C>T(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. R5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MIS18A
NM_018944.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.48

Publications

0 publications found

Variant links:

Genes affected

MIS18A (HGNC:1286): (MIS18 kinetochore protein A) Enables identical protein binding activity. Predicted to be involved in CENP-A containing chromatin assembly and chromosome segregation. Predicted to act upstream of or within regulation of DNA methylation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MIS18A links:

MIS18A-AS1 (HGNC:40106): (MIS18A antisense RNA 1)

MIS18A-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04323873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018944.3. 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
	MIS18A	NM_018944.3	MANE Select	c.13C>T	p.Arg5Trp	missense	Exon 1 of 5	NP_061817.1	Q9NYP9
	MIS18A-AS1	NR_046576.1		n.-203G>A		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIS18A	ENST00000290130.4	TSL:1 MANE Select	c.13C>T	p.Arg5Trp	missense	Exon 1 of 5	ENSP00000290130.3	Q9NYP9
MIS18A	ENST00000926599.1		c.13C>T	p.Arg5Trp	missense	Exon 1 of 5	ENSP00000596658.1
MIS18A	ENST00000956396.1		c.13C>T	p.Arg5Trp	missense	Exon 1 of 4	ENSP00000626455.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

241016

AF XY:

0.00000761

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445010

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717102

African (AFR)

AF:

0.00

AC:

AN:

33254

American (AMR)

AF:

0.00

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39382

South Asian (SAS)

AF:

0.00

AC:

AN:

85990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104596

Other (OTH)

AF:

0.00

AC:

AN:

59778

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.37

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.018

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.45

M_CAP

Benign

0.0066

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

-1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.88

REVEL

Benign

0.0040

Sift

Benign

0.18

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.11

MutPred

0.42

Loss of methylation at R5 (P = 0.0168)

MVP

0.21

MPC

0.25

ClinPred

0.058

GERP RS

-7.2

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.046

gMVP

0.075

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over