10-13171227-G-A

Variant summary

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

The NM_018518.5(MCM10):c.313G>A(p.Ala105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

Genes affected

MCM10 (HGNC:18043): (minichromosome maintenance 10 replication initiation factor) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre-RC) and it may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein can interact with MCM2 and MCM6, as well as with the origin recognition protein ORC2. It is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. Studies of a similar protein in Xenopus suggest that the chromatin binding of this protein at the onset of DNA replication is after pre-RC assembly and before origin unwinding. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

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=0.21145248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM10	NM_018518.5	c.313G>A	p.Ala105Thr	missense_variant	3/20	ENST00000378714.8
MCM10	NM_182751.3	c.313G>A	p.Ala105Thr	missense_variant	3/20
MCM10	XM_011519538.3	c.313G>A	p.Ala105Thr	missense_variant	3/20
MCM10	XM_047425437.1	c.313G>A	p.Ala105Thr	missense_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM10	ENST00000378714.8	c.313G>A	p.Ala105Thr	missense_variant	3/20	1	NM_018518.5	P4
MCM10	ENST00000484800.6	c.313G>A	p.Ala105Thr	missense_variant	3/20	1		A1
MCM10	ENST00000378694.1	c.313G>A	p.Ala105Thr	missense_variant	2/18	5
MCM10	ENST00000479669.5	c.73G>A	p.Ala25Thr	missense_variant	2/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.313G>A (p.A105T) alteration is located in exon 3 (coding exon 2) of the MCM10 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the alanine (A) at amino acid position 105 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	1.0
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.048
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.035	D;D;D;D
Sift4G	Benign	0.092	T;D;T;T
Polyphen		0.79	P;.;P;B
Vest4		0.10
MutPred		0.13		Gain of phosphorylation at A105 (P = 0.0025);.;Gain of phosphorylation at A105 (P = 0.0025);Gain of phosphorylation at A105 (P = 0.0025);
MVP		0.59
MPC		0.11
ClinPred		0.83	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.081
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-13213227;