21-32270528-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

19
Splicing: ADA: 0.00009219
2

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]

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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
MIS18ANM_018944.3 linkc.403G>A p.Val135Ile missense_variant, splice_region_variant 3/5 ENST00000290130.4 NP_061817.1 Q9NYP9
MIS18AXM_017028400.2 linkc.403G>A p.Val135Ile missense_variant, splice_region_variant 3/5 XP_016883889.1
MIS18AXM_017028401.2 linkc.403G>A p.Val135Ile missense_variant, splice_region_variant 3/5 XP_016883890.1
MIS18AXR_002958619.2 linkn.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
MIS18AENST00000290130.4 linkc.403G>A p.Val135Ile missense_variant, splice_region_variant 3/51 NM_018944.3 ENSP00000290130.3 Q9NYP9
MIS18AENST00000486363.1 linkn.51G>A non_coding_transcript_exon_variant 1/23

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152094
Hom.:
0
Cov.:
33
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:
20
AN:
204918
Hom.:
0
AF XY:
0.000134
AC XY:
15
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:
92
AN:
1395314
Hom.:
1
Cov.:
30
AF XY:
0.0000926
AC XY:
64
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:
11
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
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:
14

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 submitterclinical testingAmbry GeneticsJan 19, 2024This 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
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.099
DANN
Benign
0.41
DEOGEN2
Benign
0.019
T
Eigen
Benign
-2.0
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0080
N
LIST_S2
Benign
0.46
T
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.012
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-2.3
N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.010
N
REVEL
Benign
0.036
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.11
MutPred
0.12
Loss of disorder (P = 0.1359);
MVP
0.26
MPC
0.20
ClinPred
0.017
T
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.

Other links and lift over

dbSNP: rs573480187; hg19: chr21-33642839; API