21-46235113-A-C

Position:

• chr21-46235113-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000420074.1(MCM3AP-AS1):​n.1607A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 837,586 control chromosomes in the GnomAD database, including 58,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8733 hom., cov: 33)
  • Exomes 𝑓: 0.37 (49535 hom.)
• Consequence: MCM3AP-AS1 ENST00000420074.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.140

Genes affected

MCM3AP-AS1 (HGNC:):

MCM3AP (HGNC:6946): (minichromosome maintenance complex component 3 associated protein) The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 21-46235113-A-C is Benign according to our data. Variant chr21-46235113-A-C is described in ClinVar as [Benign]. Clinvar id is 1228038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM3AP	NM_003906.5	c.*155T>G		downstream_gene_variant		ENST00000291688.6	NP_003897.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM3AP	ENST00000291688.6	c.*155T>G		downstream_gene_variant		1	NM_003906.5	ENSP00000291688.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49469 AN: 152054 Hom.: 8726 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.372 AC: 255211 AN: 685414 Hom.: 49535 Cov.: 9 AF XY: 0.373 AC XY: 130611 AN XY: 349776

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.391

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.325 AC: 49513 AN: 152172 Hom.: 8733 Cov.: 33 AF XY: 0.321 AC XY: 23874 AN XY: 74412

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.346

Alfa AF: 0.380 Hom.: 18711

Bravo AF: 0.315

Asia WGS AF: 0.253 AC: 882 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.5
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2298695; hg19: chr21-47655027;