Variant 21-32270497-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018944.3(MIS18A):c.434C>T(p.Ser145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,607,066 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

MIS18A
NM_018944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14222848).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MIS18A	NM_018944.3 linkuse as main transcript	c.434C>T	p.Ser145Leu	missense_variant	3/5	ENST00000290130.4	NP_061817.1
MIS18A	XM_017028400.2 linkuse as main transcript	c.434C>T	p.Ser145Leu	missense_variant	3/5		XP_016883889.1
MIS18A	XM_017028401.2 linkuse as main transcript	c.434C>T	p.Ser145Leu	missense_variant	3/5		XP_016883890.1
MIS18A	XR_002958619.2 linkuse as main transcript	n.469C>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIS18A	ENST00000290130.4 linkuse as main transcript	c.434C>T	p.Ser145Leu	missense_variant	3/5	1	NM_018944.3	ENSP00000290130	P1
MIS18A	ENST00000486363.1 linkuse as main transcript	n.82C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000300

AC:

AN:

243080

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

131596

show subpopulations

Gnomad AFR exome

AF:

0.0000636

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000189

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.000188

AC:

273

AN:

1454842

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

129

AN XY:

723740

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000106

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.000433

GnomAD4 genome

AF:

0.000355

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.000468

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

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

Oct 26, 2021

The c.434C>T (p.S145L) alteration is located in exon 3 (coding exon 3) of the MIS18A gene. This alteration results from a C to T substitution at nucleotide position 434, causing the serine (S) at amino acid position 145 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

0.12

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Benign

0.025

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.23

Sift

Benign

0.032

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.40

MVP

0.58

MPC

0.29

ClinPred

0.15

GERP RS

5.8

Varity_R

0.18

gMVP

0.33

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