Genetic Variant NM_018944.3:c.403G>T (chr21-32270528-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018944.3(MIS18A):c.403G>T(p.Val135Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V135I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MIS18A
NM_018944.3 missense, splice_region

Scores

Splicing: ADA: 0.00001017

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.09

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.101810366).

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.403G>T	p.Val135Phe	missense splice_region	Exon 3 of 5	NP_061817.1	Q9NYP9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIS18A	ENST00000290130.4	TSL:1 MANE Select	c.403G>T	p.Val135Phe	missense splice_region	Exon 3 of 5	ENSP00000290130.3	Q9NYP9
MIS18A	ENST00000926599.1		c.412G>T	p.Val138Phe	missense splice_region	Exon 3 of 5	ENSP00000596658.1
MIS18A	ENST00000956396.1		c.402-725G>T		intron	N/A	ENSP00000626455.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395312

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29962

American (AMR)

AF:

0.00

AC:

AN:

31168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23282

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37772

South Asian (SAS)

AF:

0.00

AC:

AN:

76944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081680

Other (OTH)

AF:

0.00

AC:

AN:

57278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.4

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.054

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.67

M_CAP

Benign

0.013

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

REVEL

Benign

0.14

Sift

Benign

0.044

Sift4G

Uncertain

0.032

Polyphen

0.14

Vest4

0.48

MutPred

0.12

Loss of disorder (P = 0.1424)

MVP

0.22

MPC

0.46

ClinPred

0.17

GERP RS

-6.8

Varity_R

0.083

gMVP

0.45

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000010

dbscSNV1_RF

Benign

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over