21-32270528-C-T

Position:

chr21-32270528-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_018944.3(MIS18A):c.403G>A(p.Val135Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000666 in 1,547,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

MIS18A
NM_018944.3 missense, splice_region

Scores

Splicing: ADA: 0.00009219

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.09

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012464076).

BP6

Variant 21-32270528-C-T is Benign according to our data. Variant chr21-32270528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3126716.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIS18A	NM_018944.3 link	c.403G>A	p.Val135Ile	missense_variant, splice_region_variant	3/5	ENST00000290130.4	NP_061817.1	Q9NYP9
MIS18A	XM_017028400.2 link	c.403G>A	p.Val135Ile	missense_variant, splice_region_variant	3/5		XP_016883889.1
MIS18A	XM_017028401.2 link	c.403G>A	p.Val135Ile	missense_variant, splice_region_variant	3/5		XP_016883890.1
MIS18A	XR_002958619.2 link	n.438G>A		splice_region_variant, non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIS18A	ENST00000290130.4 link	c.403G>A	p.Val135Ile	missense_variant, splice_region_variant	3/5	1	NM_018944.3	ENSP00000290130.3		Q9NYP9
MIS18A	ENST00000486363.1 link	n.51G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000976

AC:

AN:

204918

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

112062

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:

0.000782

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000427

GnomAD4 exome

AF:

0.0000659

AC:

AN:

1395314

Hom.:

Cov.:

AF XY:

0.0000926

AC XY:

AN XY:

691192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000334

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000265

Gnomad4 SAS exome

AF:

0.00100

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000370

Gnomad4 OTH exome

AF:

0.0000698

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.099

DANN

Benign

0.41

DEOGEN2

Benign

0.019

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.46

M_CAP

Benign

0.0037

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

PrimateAI

Benign

0.35

PROVEAN

Benign

0.010

REVEL

Benign

0.036

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MutPred

0.12

Loss of disorder (P = 0.1359);

MVP

0.26

MPC

0.20

ClinPred

0.017

GERP RS

-6.8

Varity_R

0.011

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000092

dbscSNV1_RF

Benign

0.0040

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