Genetic Variant NM_018518.5:c.67G>T (chr10-13170981-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018518.5(MCM10):c.67G>T(p.Asp23Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MCM10
NM_018518.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Variant links:

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]

MCM10 links:

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ACMG classification

Classification made for transcript

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=0.07107556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM10	NM_018518.5 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20	ENST00000378714.8	NP_060988.3	Q7L590-2
MCM10	NM_182751.3 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20		NP_877428.1	Q7L590-1
MCM10	XM_011519538.3 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20		XP_011517840.1	Q7L590-1
MCM10	XM_047425437.1 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCM10	ENST00000378714.8 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20	1	NM_018518.5	ENSP00000367986.3	Q7L590-2
MCM10	ENST00000484800.6 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 3 of 20	1		ENSP00000418268.1	Q7L590-1
MCM10	ENST00000378694.1 link	c.67G>T	p.Asp23Tyr	missense_variant	Exon 2 of 18	5		ENSP00000367966.1	Q5T670
MCM10	ENST00000479669 link	c.-174G>T		5_prime_UTR_variant	Exon 2 of 3	4		ENSP00000417094.1	C9J600

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251350

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135864

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

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:

0.0000941

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000660

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.10

.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.064

Sift

Uncertain

0.029

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.31

B;B;B

Vest4

0.26

MutPred

0.20

Gain of catalytic residue at D23 (P = 0.0298);Gain of catalytic residue at D23 (P = 0.0298);Gain of catalytic residue at D23 (P = 0.0298);

MVP

0.41

MPC

0.17

ClinPred

0.11

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.064

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over