rs2307340

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006739.4(MCM5):c.539C>G(p.Thr180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,611,746 control chromosomes in the GnomAD database, including 5,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.062 ( 385 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5120 hom. )

Consequence

MCM5
NM_006739.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.169

Variant links:

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

MCM5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018073916).

BP6

Variant 22-35406668-C-G is Benign according to our data. Variant chr22-35406668-C-G is described in ClinVar as [Benign]. Clinvar id is 1674156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MCM5	NM_006739.4 linkuse as main transcript	c.539C>G	p.Thr180Ser	missense_variant	5/17	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5 linkuse as main transcript	c.539C>G	p.Thr180Ser	missense_variant	5/18		XP_006724305.1
MCM5	XM_047441366.1 linkuse as main transcript	c.539C>G	p.Thr180Ser	missense_variant	5/18		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9 linkuse as main transcript	c.539C>G	p.Thr180Ser	missense_variant	5/17	1	NM_006739.4	ENSP00000216122	P1

Frequencies

GnomAD3 genomes

AF:

0.0615

AC:

9368

AN:

152206

Hom.:

385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0268

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.0758

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0864

Gnomad OTH

AF:

0.0660

GnomAD3 exomes

AF:

0.0633

AC:

15779

AN:

249334

Hom.:

693

AF XY:

0.0664

AC XY:

8960

AN XY:

134988

show subpopulations

Gnomad AFR exome

AF:

0.0246

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0267

Gnomad EAS exome

AF:

0.00288

Gnomad SAS exome

AF:

0.0772

Gnomad FIN exome

AF:

0.0948

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.0685

GnomAD4 exome

AF:

0.0795

AC:

116059

AN:

1459422

Hom.:

5120

Cov.:

AF XY:

0.0799

AC XY:

58000

AN XY:

726150

show subpopulations

Gnomad4 AFR exome

AF:

0.0224

Gnomad4 AMR exome

AF:

0.0289

Gnomad4 ASJ exome

AF:

0.0260

Gnomad4 EAS exome

AF:

0.00438

Gnomad4 SAS exome

AF:

0.0762

Gnomad4 FIN exome

AF:

0.0946

Gnomad4 NFE exome

AF:

0.0874

Gnomad4 OTH exome

AF:

0.0717

GnomAD4 genome

AF:

0.0615

AC:

9371

AN:

152324

Hom.:

385

Cov.:

AF XY:

0.0613

AC XY:

4562

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0268

Gnomad4 AMR

AF:

0.0433

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.00482

Gnomad4 SAS

AF:

0.0763

Gnomad4 FIN

AF:

0.101

Gnomad4 NFE

AF:

0.0864

Gnomad4 OTH

AF:

0.0653

Alfa

AF:

0.0677

Hom.:

293

Bravo

AF:

0.0541

TwinsUK

AF:

0.0847

AC:

314

ALSPAC

AF:

0.0846

AC:

326

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.0855

AC:

735

ExAC

AF:

0.0657

AC:

7971

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

EpiCase

AF:

0.0792

EpiControl

AF:

0.0781

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

MCM5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.043

T;T;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.42

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.0

N;.;.;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.12

N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.75

T;T;T;T

Sift4G

Benign

0.75

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.082

MutPred

0.25

Gain of helix (P = 0.0425);.;.;.;

MPC

0.32

ClinPred

0.0010

GERP RS

0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.036

gMVP

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over