21-32270514-C-T

Variant names:

• chr21-32270514-C-T
• rs750243774
• NM_018944.3:c.417G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_018944.3(MIS18A):​c.417G>A​(p.Leu139Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,438,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MIS18A NM_018944.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.

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.417G>A	p.Leu139Leu	synonymous	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.417G>A	p.Leu139Leu	synonymous	Exon 3 of 5	ENSP00000290130.3	Q9NYP9
	MIS18A	ENST00000926599.1		c.426G>A	p.Leu142Leu	synonymous	Exon 3 of 5	ENSP00000596658.1
	MIS18A	ENST00000956396.1		c.402-711G>A		intron	N/A	ENSP00000626455.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1438002 Hom.: 0 Cov.: 30 AF XY: 0.0000182 AC XY: 13 AN XY: 714600

African (AFR) AF: 0.00 AC: 0 AN: 32070

American (AMR) AF: 0.00 AC: 0 AN: 39144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25064

East Asian (EAS) AF: 0.00 AC: 0 AN: 38994

South Asian (SAS) AF: 0.00 AC: 0 AN: 82204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.0000181 AC: 20 AN: 1102534

Other (OTH) AF: 0.00 AC: 0 AN: 59332

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.8
DANN	Benign	0.52
PhyloP100		-1.1

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: rs750243774; hg19: chr21-33642825;