21-32270497-G-A

Variant names:

• chr21-32270497-G-A
• rs200789498
• NM_018944.3:c.434C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14222848).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.434C>T	p.Ser145Leu	missense	Exon 3 of 5	NP_061817.1	Q9NYP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIS18A	ENST00000290130.4	TSL:1 MANE Select	c.434C>T	p.Ser145Leu	missense	Exon 3 of 5	ENSP00000290130.3	Q9NYP9
	MIS18A	ENST00000926599.1		c.443C>T	p.Ser148Leu	missense	Exon 3 of 5	ENSP00000596658.1
	MIS18A	ENST00000956396.1		c.402-694C>T		intron	N/A	ENSP00000626455.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152106 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000300 AC: 73 AN: 243080 AF XY: 0.000258

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 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.: 2 Cov.: 30 AF XY: 0.000178 AC XY: 129 AN XY: 723740

African (AFR) AF: 0.000121 AC: 4 AN: 32946

American (AMR) AF: 0.00109 AC: 47 AN: 43150

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.000106 AC: 9 AN: 84960

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53318

Middle Eastern (MID) AF: 0.00907 AC: 52 AN: 5732

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1109376

Other (OTH) AF: 0.000433 AC: 26 AN: 60090

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74444

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.00196 AC: 30 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68010

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.23
Sift	Benign	0.032	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.40
MVP		0.58
MPC		0.29
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.18
gMVP		0.33
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs200789498; hg19: chr21-33642808; COSMIC: COSV51590027;