rs7905784

Positions:

• chr10-13192356-A-T

Variant summary

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

The NM_018518.5(MCM10):​c.1618A>T​(p.Thr540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,626 control chromosomes in the GnomAD database, including 18,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1393 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17113 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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=0.0028232634).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM10	NM_018518.5	c.1618A>T	p.Thr540Ser	missense_variant	12/20	ENST00000378714.8	NP_060988.3
MCM10	NM_182751.3	c.1621A>T	p.Thr541Ser	missense_variant	12/20		NP_877428.1
MCM10	XM_011519538.3	c.1621A>T	p.Thr541Ser	missense_variant	12/20		XP_011517840.1
MCM10	XM_047425437.1	c.1618A>T	p.Thr540Ser	missense_variant	12/20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM10	ENST00000378714.8	c.1618A>T	p.Thr540Ser	missense_variant	12/20	1	NM_018518.5	ENSP00000367986	P4
MCM10	ENST00000484800.6	c.1621A>T	p.Thr541Ser	missense_variant	12/20	1		ENSP00000418268	A1
MCM10	ENST00000378694.1	c.1618A>T	p.Thr540Ser	missense_variant	11/18	5		ENSP00000367966

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18592 AN: 152012 Hom.: 1392 Cov.: 32

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.0868

GnomAD3 exomes AF: 0.115 AC: 28832 AN: 251270 Hom.: 2295 AF XY: 0.114 AC XY: 15510 AN XY: 135790

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.0467

Gnomad ASJ exome AF: 0.0525

Gnomad EAS exome AF: 0.0264

Gnomad SAS exome AF: 0.0418

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.144 AC: 210785 AN: 1461496 Hom.: 17113 Cov.: 32 AF XY: 0.141 AC XY: 102822 AN XY: 727084

Gnomad4 AFR exome AF: 0.0798

Gnomad4 AMR exome AF: 0.0493

Gnomad4 ASJ exome AF: 0.0521

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0417

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.122 AC: 18610 AN: 152130 Hom.: 1393 Cov.: 32 AF XY: 0.121 AC XY: 9030 AN XY: 74358

Gnomad4 AFR AF: 0.0834

Gnomad4 AMR AF: 0.0677

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.0374

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.0859

Alfa AF: 0.144 Hom.: 1377

Bravo AF: 0.108

TwinsUK AF: 0.163 AC: 606

ALSPAC AF: 0.159 AC: 614

ESP6500AA AF: 0.0881 AC: 388

ESP6500EA AF: 0.146 AC: 1258

ExAC AF: 0.118 AC: 14272

Asia WGS AF: 0.0380 AC: 132 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.0
DANN	Benign	0.29
DEOGEN2	Benign	0.030	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.35	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	.;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.020
MPC		0.091
ClinPred		0.0011	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7905784; hg19: chr10-13234356; COSMIC: COSV66334815; COSMIC: COSV66334815;