rs9975588

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003906.5(MCM3AP):c.305C>T(p.Ser102Leu) variant causes a missense change. The variant allele was found at a frequency of 0.361 in 1,613,854 control chromosomes in the GnomAD database, including 108,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S102S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 8154 hom., cov: 33)

Exomes 𝑓: 0.37 ( 100819 hom. )

Consequence

MCM3AP
NM_003906.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.82

Publications

45 publications found

Variant links:

Genes affected

MCM3AP (HGNC:6946): (minichromosome maintenance complex component 3 associated protein) The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability. [provided by RefSeq, Jan 2014]

MCM3AP Gene-Disease associations (from GenCC):

peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

MCM3AP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003872782).

BP6

Variant 21-46284982-G-A is Benign according to our data. Variant chr21-46284982-G-A is described in ClinVar as Benign. ClinVar VariationId is 403613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003906.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3AP	NM_003906.5	MANE Select	c.305C>T	p.Ser102Leu	missense	Exon 1 of 28	NP_003897.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCM3AP	ENST00000291688.6	TSL:1 MANE Select	c.305C>T	p.Ser102Leu	missense	Exon 1 of 28	ENSP00000291688.1	O60318-1
MCM3AP	ENST00000397708.1	TSL:5	c.305C>T	p.Ser102Leu	missense	Exon 2 of 29	ENSP00000380820.1	O60318-1
MCM3AP	ENST00000426537.1	TSL:2	c.*23C>T		downstream_gene	N/A	ENSP00000408934.1	A0A0A0MSZ7

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47592

AN:

152028

Hom.:

8156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.497

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.375

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.346

GnomAD2 exomes

AF:

0.319

AC:

80178

AN:

251278

AF XY:

0.326

show subpopulations

Gnomad AFR exome

AF:

0.207

Gnomad AMR exome

AF:

0.231

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.299

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.366

AC:

534397

AN:

1461708

Hom.:

100819

Cov.:

AF XY:

0.365

AC XY:

265292

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.210

AC:

7045

AN:

33480

American (AMR)

AF:

0.235

AC:

10503

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

9890

AN:

26136

East Asian (EAS)

AF:

0.112

AC:

4465

AN:

39700

South Asian (SAS)

AF:

0.294

AC:

25324

AN:

86256

European-Finnish (FIN)

AF:

0.306

AC:

16328

AN:

53316

Middle Eastern (MID)

AF:

0.398

AC:

2298

AN:

5768

European-Non Finnish (NFE)

AF:

0.393

AC:

437529

AN:

1111940

Other (OTH)

AF:

0.348

AC:

21015

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

20375

40750

61126

81501

101876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13404

26808

40212

53616

67020

<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:

0.313

AC:

47606

AN:

152146

Hom.:

8154

Cov.:

AF XY:

0.305

AC XY:

22703

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.212

AC:

8786

AN:

41516

American (AMR)

AF:

0.281

AC:

4297

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

1303

AN:

3472

East Asian (EAS)

AF:

0.131

AC:

679

AN:

5186

South Asian (SAS)

AF:

0.276

AC:

1330

AN:

4818

European-Finnish (FIN)

AF:

0.293

AC:

3096

AN:

10578

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.395

AC:

26821

AN:

67978

Other (OTH)

AF:

0.346

AC:

731

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1680

3360

5041

6721

8401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.359

Hom.:

17964

Bravo

AF:

0.309

TwinsUK

AF:

0.403

AC:

1496

ALSPAC

AF:

0.399

AC:

1536

ESP6500AA

AF:

0.213

AC:

940

ESP6500EA

AF:

0.392

AC:

3371

ExAC

AF:

0.324

AC:

39330

Asia WGS

AF:

0.213

AC:

743

AN:

3478

EpiCase

AF:

0.391

EpiControl

AF:

0.400

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

PhyloP100

4.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

REVEL

Benign

0.045

Sift

Uncertain

0.020

Sift4G

Uncertain

0.038

Polyphen

0.84

Vest4

0.38

MPC

0.16

ClinPred

0.029

GERP RS

4.6

Varity_R

0.15

gMVP

0.24

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over