chr21-46235293-G-A

Position:

• chr21-46235293-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003906.5(MCM3AP):​c.5918C>T​(p.Ala1973Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MCM3AP NM_003906.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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

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=0.16342106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM3AP	NM_003906.5	c.5918C>T	p.Ala1973Val	missense_variant	28/28	ENST00000291688.6	NP_003897.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM3AP	ENST00000291688.6	c.5918C>T	p.Ala1973Val	missense_variant	28/28	1	NM_003906.5	ENSP00000291688.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1973 of the MCM3AP protein (p.Ala1973Val). This variant is present in population databases (rs763969969, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MCM3AP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.038
Sift	Benign	0.065	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.033	B;B
Vest4		0.19
MutPred		0.41		Gain of catalytic residue at A1973 (P = 0.0032);Gain of catalytic residue at A1973 (P = 0.0032);
MVP		0.22
MPC		0.12
ClinPred		0.31	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.29

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: rs763969969; hg19: chr21-47655207; COSMIC: COSV52439112;