10-13172436-C-T

Position:

• chr10-13172436-C-T

Variant summary

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

The NM_018518.5(MCM10):​c.410C>T​(p.Thr137Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

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=0.17588338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM10	NM_018518.5	c.410C>T	p.Thr137Ile	missense_variant	4/20	ENST00000378714.8	NP_060988.3
MCM10	NM_182751.3	c.410C>T	p.Thr137Ile	missense_variant	4/20		NP_877428.1
MCM10	XM_011519538.3	c.410C>T	p.Thr137Ile	missense_variant	4/20		XP_011517840.1
MCM10	XM_047425437.1	c.410C>T	p.Thr137Ile	missense_variant	4/20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM10	ENST00000378714.8	c.410C>T	p.Thr137Ile	missense_variant	4/20	1	NM_018518.5	ENSP00000367986	P4
MCM10	ENST00000484800.6	c.410C>T	p.Thr137Ile	missense_variant	4/20	1		ENSP00000418268	A1
MCM10	ENST00000378694.1	c.410C>T	p.Thr137Ile	missense_variant	3/18	5		ENSP00000367966
MCM10	ENST00000479669.5	c.170C>T	p.Thr57Ile	missense_variant	3/3	4		ENSP00000417094

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000189

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

Apr 07, 2022

The c.410C>T (p.T137I) alteration is located in exon 4 (coding exon 3) of the MCM10 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the threonine (T) at amino acid position 137 to be replaced by an isoleucine (I). 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	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T;T;.
Eigen	Benign	-0.0090
Eigen_PC	Benign	0.065
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	0.93	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;D;N;N
REVEL	Benign	0.083
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.43	B;.;B;B
Vest4		0.095
MutPred		0.18		Loss of phosphorylation at T137 (P = 0.0272);.;Loss of phosphorylation at T137 (P = 0.0272);Loss of phosphorylation at T137 (P = 0.0272);
MVP		0.56
MPC		0.26
ClinPred		0.38	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.088
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1384727466; hg19: chr10-13214436;