NM_003906.5:c.2931T>C

Variant names:

• chr21-46266025-A-G
• rs2839181
• NM_003906.5:c.2931T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003906.5(MCM3AP):​c.2931T>C​(p.His977His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,610,844 control chromosomes in the GnomAD database, including 171,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16869 hom., cov: 32)
  • Exomes 𝑓: 0.46 (154885 hom.)
• Consequence: MCM3AP NM_003906.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.256
• Publications: 32 publications found

Genes affected

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]

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-46266025-A-G is Benign according to our data. Variant chr21-46266025-A-G is described in ClinVar as Benign. ClinVar VariationId is 403075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.256 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003906.5. 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
	MCM3AP	NM_003906.5	MANE Select	c.2931T>C	p.His977His	synonymous	Exon 11 of 28	NP_003897.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3AP	ENST00000291688.6	TSL:1 MANE Select	c.2931T>C	p.His977His	synonymous	Exon 11 of 28	ENSP00000291688.1	O60318-1
	MCM3AP	ENST00000397708.1	TSL:5	c.2931T>C	p.His977His	synonymous	Exon 12 of 29	ENSP00000380820.1	O60318-1
	MCM3AP	ENST00000486937.5	TSL:2	n.1223T>C		non_coding_transcript_exon	Exon 2 of 18

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71047 AN: 151866 Hom.: 16862 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.457 AC: 114341 AN: 249964 AF XY: 0.450

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.458 AC: 668527 AN: 1458862 Hom.: 154885 Cov.: 46 AF XY: 0.455 AC XY: 330023 AN XY: 725486

African (AFR) AF: 0.501 AC: 16764 AN: 33472

American (AMR) AF: 0.556 AC: 24763 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12574 AN: 26106

East Asian (EAS) AF: 0.249 AC: 9864 AN: 39678

South Asian (SAS) AF: 0.391 AC: 33333 AN: 85176

European-Finnish (FIN) AF: 0.480 AC: 25554 AN: 53224

Middle Eastern (MID) AF: 0.429 AC: 2471 AN: 5764

European-Non Finnish (NFE) AF: 0.464 AC: 515632 AN: 1110602

Other (OTH) AF: 0.457 AC: 27572 AN: 60306

GnomAD4 genome AF: 0.468 AC: 71074 AN: 151982 Hom.: 16869 Cov.: 32 AF XY: 0.467 AC XY: 34676 AN XY: 74286

African (AFR) AF: 0.501 AC: 20745 AN: 41448

American (AMR) AF: 0.501 AC: 7653 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1626 AN: 3470

East Asian (EAS) AF: 0.285 AC: 1470 AN: 5150

South Asian (SAS) AF: 0.386 AC: 1859 AN: 4816

European-Finnish (FIN) AF: 0.487 AC: 5150 AN: 10580

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31243 AN: 67928

Other (OTH) AF: 0.447 AC: 943 AN: 2110

Alfa AF: 0.466 Hom.: 26592

Bravo AF: 0.471

Asia WGS AF: 0.334 AC: 1166 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.452

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.47
DANN	Benign	0.34
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=95/5	polymorphism (auto)

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: rs2839181; hg19: chr21-47685939; COSMIC: COSV52437028; COSMIC: COSV52437028;