Variant 21-32278998-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018944.3(MIS18A):c.17C>T(p.Ser6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,600,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MIS18A
NM_018944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0140

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17733666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MIS18A	NM_018944.3 linkuse as main transcript	c.17C>T	p.Ser6Leu	missense_variant	1/5	ENST00000290130.4	NP_061817.1
MIS18A	XM_017028400.2 linkuse as main transcript	c.17C>T	p.Ser6Leu	missense_variant	1/5		XP_016883889.1
MIS18A	XM_017028401.2 linkuse as main transcript	c.17C>T	p.Ser6Leu	missense_variant	1/5		XP_016883890.1
MIS18A	XR_002958619.2 linkuse as main transcript	n.52C>T		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIS18A	ENST00000290130.4 linkuse as main transcript	c.17C>T	p.Ser6Leu	missense_variant	1/5	1	NM_018944.3	ENSP00000290130	P1
MIS18A-AS1	ENST00000453549.1 linkuse as main transcript	n.373+467G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1447804

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

718708

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

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:

0.0000317

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.17C>T (p.S6L) alteration is located in exon 1 (coding exon 1) of the MIS18A gene. This alteration results from a C to T substitution at nucleotide position 17, causing the serine (S) at amino acid position 6 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.49

M_CAP

Benign

0.019

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

REVEL

Benign

0.084

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

0.87

Vest4

0.11

MutPred

0.32

Loss of phosphorylation at S6 (P = 0.0221);

MVP

0.57

MPC

0.30

ClinPred

0.36

GERP RS

3.8

Varity_R

0.080

gMVP

0.13

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

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