Genetic Variant NM_005916.5:c.431A>G (chr7-100099174-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005916.5(MCM7):c.431A>G(p.Asn144Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,792 control chromosomes in the GnomAD database, including 57,993 homozygotes. 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 0.20 ( 3891 hom., cov: 30)

Exomes 𝑓: 0.27 ( 54102 hom. )

Consequence

MCM7
NM_005916.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0440

Publications

54 publications found

Variant links:

Genes affected

MCM7 (HGNC:6950): (minichromosome maintenance complex component 7) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 6 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. Cyclin D1-dependent kinase, CDK4, is found to associate with this protein, and may regulate the binding of this protein with the tumorsuppressor protein RB1/RB. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

MCM7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021751225).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM7	NM_005916.5 link	c.431A>G	p.Asn144Ser	missense_variant	Exon 5 of 15	ENST00000303887.10	NP_005907.3	P33993-1C6EMX8A0A0S2Z4A5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM7	ENST00000303887.10 link	c.431A>G	p.Asn144Ser	missense_variant	Exon 5 of 15	1	NM_005916.5	ENSP00000307288.5		P33993-1

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30788

AN:

151882

Hom.:

3889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0547

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.247

Gnomad FIN

AF:

0.295

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.239

AC:

60161

AN:

251466

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.260

Gnomad FIN exome

AF:

0.299

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.245

GnomAD4 exome

AF:

0.267

AC:

390920

AN:

1461792

Hom.:

54102

Cov.:

AF XY:

0.267

AC XY:

193993

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0424

AC:

1421

AN:

33480

American (AMR)

AF:

0.164

AC:

7344

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6434

AN:

26136

East Asian (EAS)

AF:

0.264

AC:

10467

AN:

39700

South Asian (SAS)

AF:

0.234

AC:

20215

AN:

86256

European-Finnish (FIN)

AF:

0.296

AC:

15808

AN:

53416

Middle Eastern (MID)

AF:

0.146

AC:

841

AN:

5768

European-Non Finnish (NFE)

AF:

0.282

AC:

313494

AN:

1111920

Other (OTH)

AF:

0.247

AC:

14896

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

16488

32976

49463

65951

82439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10302

20604

30906

41208

51510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.203

AC:

30793

AN:

152000

Hom.:

3891

Cov.:

AF XY:

0.203

AC XY:

15097

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0545

AC:

2263

AN:

41498

American (AMR)

AF:

0.173

AC:

2644

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3470

East Asian (EAS)

AF:

0.269

AC:

1388

AN:

5154

South Asian (SAS)

AF:

0.247

AC:

1189

AN:

4818

European-Finnish (FIN)

AF:

0.295

AC:

3113

AN:

10556

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.275

AC:

18679

AN:

67936

Other (OTH)

AF:

0.199

AC:

417

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1187

2373

3560

4746

5933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.250

Hom.:

16594

Bravo

AF:

0.187

TwinsUK

AF:

0.299

AC:

1110

ALSPAC

AF:

0.276

AC:

1065

ESP6500AA

AF:

0.0651

AC:

287

ESP6500EA

AF:

0.286

AC:

2459

ExAC

AF:

0.238

AC:

28943

Asia WGS

AF:

0.277

AC:

967

AN:

3478

EpiCase

AF:

0.266

EpiControl

AF:

0.273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.2

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.027

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.6

N;N;.

PhyloP100

0.044

PrimateAI

Benign

0.36

PROVEAN

Benign

0.84

N;N;N

REVEL

Benign

0.021

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.75

T;T;.

Polyphen

0.0

.;B;.

Vest4

0.082

MPC

0.10

ClinPred

0.0010

GERP RS

-3.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.086

gMVP

0.21

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over