chr21-32270528-C-A

Variant names:

• chr21-32270528-C-A
• rs573480187
• NM_018944.3:c.403G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 17/22 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101810366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIS18A	NM_018944.3	c.403G>T	p.Val135Phe	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000290130.4	NP_061817.1
MIS18A	XM_017028400.2	c.403G>T	p.Val135Phe	missense_variant, splice_region_variant	Exon 3 of 5		XP_016883889.1
MIS18A	XM_017028401.2	c.403G>T	p.Val135Phe	missense_variant, splice_region_variant	Exon 3 of 5		XP_016883890.1
MIS18A	XR_002958619.2	n.438G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIS18A	ENST00000290130.4	c.403G>T	p.Val135Phe	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_018944.3	ENSP00000290130.3
MIS18A	ENST00000486363.1	n.51G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395312 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.4
DANN	Benign	0.84
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Benign	0.044	D
Sift4G	Uncertain	0.032	D
Polyphen		0.14	B
Vest4		0.48
MutPred		0.12		Loss of disorder (P = 0.1424);
MVP		0.22
MPC		0.46
ClinPred		0.17	T
GERP RS		-6.8
Varity_R		0.083
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs573480187; hg19: chr21-33642839;