21-32278825-T-G

Variant names:

• chr21-32278825-T-G
• rs151033812
• NM_018944.3:c.190A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018944.3(MIS18A):​c.190A>C​(p.Met64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MIS18A NM_018944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.598

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04782933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIS18A	NM_018944.3	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 5	ENST00000290130.4	NP_061817.1
MIS18A	XM_017028400.2	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 5		XP_016883889.1
MIS18A	XM_017028401.2	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 5		XP_016883890.1
MIS18A	XR_002958619.2	n.225A>C		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIS18A	ENST00000290130.4	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 5	1	NM_018944.3	ENSP00000290130.3
MIS18A-AS1	ENST00000453549.1	n.373+294T>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228548 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124604

Gnomad AFR exome AF: 0.0000707

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721212

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.3
DANN	Benign	0.53
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.024
Sift	Benign	0.41	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.18		Loss of loop (P = 0.0153);
MVP		0.19
MPC		0.23
ClinPred		0.028	T
GERP RS		-5.7
Varity_R		0.19
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs151033812; hg19: chr21-33651136;