MIS18A p.Met64Leu

Variant names:

• chr21-32278825-T-A
• NM_018944.3:c.190A>T
• MIS18A p.Met64Leu

Your query was ambiguous. Multiple possible variants found:

• chr21-32278825-T-A
• chr21-32278825-T-G
• chr21-32278823-CAT-TAA
• chr21-32278823-CAT-AAG
• chr21-32278823-CAT-GAG
• chr21-32278823-CAT-TAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018944.3(MIS18A):​c.190A>T​(p.Met64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. M64T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIS18A NM_018944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.598
• Publications: 0 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]

MIS18A-AS1 (HGNC:40106): (MIS18A antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050181538).

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.190A>T	p.Met64Leu	missense	Exon 1 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.190A>T	p.Met64Leu	missense	Exon 1 of 5	ENSP00000290130.3	Q9NYP9
	MIS18A	ENST00000926599.1		c.190A>T	p.Met64Leu	missense	Exon 1 of 5	ENSP00000596658.1
	MIS18A	ENST00000956396.1		c.190A>T	p.Met64Leu	missense	Exon 1 of 4	ENSP00000626455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.0
DANN	Benign	0.54
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.60
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.025
Sift	Benign	0.41	T
Sift4G	Benign	0.35	T
PromoterAI		-0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.14
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-33651136;