chr10-13172427-A-G

Position:

• chr10-13172427-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018518.5(MCM10):​c.401A>G​(p.Lys134Arg) variant causes a missense change. The variant allele was found at a frequency of 0.054 in 1,613,844 control chromosomes in the GnomAD database, including 2,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.042 (186 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2522 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015130937).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM10	NM_018518.5	c.401A>G	p.Lys134Arg	missense_variant	4/20	ENST00000378714.8	NP_060988.3
MCM10	NM_182751.3	c.401A>G	p.Lys134Arg	missense_variant	4/20		NP_877428.1
MCM10	XM_011519538.3	c.401A>G	p.Lys134Arg	missense_variant	4/20		XP_011517840.1
MCM10	XM_047425437.1	c.401A>G	p.Lys134Arg	missense_variant	4/20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM10	ENST00000378714.8	c.401A>G	p.Lys134Arg	missense_variant	4/20	1	NM_018518.5	ENSP00000367986.3
MCM10	ENST00000484800.6	c.401A>G	p.Lys134Arg	missense_variant	4/20	1		ENSP00000418268.1
MCM10	ENST00000378694.1	c.401A>G	p.Lys134Arg	missense_variant	3/18	5		ENSP00000367966.1
MCM10	ENST00000479669.5	c.161A>G	p.Lys54Arg	missense_variant	3/3	4		ENSP00000417094.1

Frequencies

GnomAD3 genomes AF: 0.0424 AC: 6447 AN: 152188 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0563 AC: 14124 AN: 250788 Hom.: 553 AF XY: 0.0573 AC XY: 7779 AN XY: 135680

Gnomad AFR exome AF: 0.00988

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.0744

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0646

GnomAD4 exome AF: 0.0552 AC: 80631 AN: 1461536 Hom.: 2522 Cov.: 31 AF XY: 0.0558 AC XY: 40575 AN XY: 727094

Gnomad4 AFR exome AF: 0.00848

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.0672

Gnomad4 EAS exome AF: 0.00141

Gnomad4 SAS exome AF: 0.0761

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0555

Gnomad4 OTH exome AF: 0.0545

GnomAD4 genome AF: 0.0424 AC: 6456 AN: 152308 Hom.: 186 Cov.: 32 AF XY: 0.0421 AC XY: 3135 AN XY: 74488

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0763

Gnomad4 ASJ AF: 0.0594

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0674

Gnomad4 FIN AF: 0.0368

Gnomad4 NFE AF: 0.0551

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0533 Hom.: 357

Bravo AF: 0.0454

TwinsUK AF: 0.0583 AC: 216

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0594 AC: 511

ExAC AF: 0.0534 AC: 6483

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.0561

EpiControl AF: 0.0525

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	.;T;T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.032	D;T;D;D
Sift4G	Benign	0.082	T;D;T;T
Polyphen		0.51	P;.;B;P
Vest4		0.040
MPC		0.084
ClinPred		0.029	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17152897; hg19: chr10-13214427;