rs9975588

Positions:

chr21-46284982-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM3AP	NM_003906.5 link	c.305C>T	p.Ser102Leu	missense_variant	1/28	ENST00000291688.6	NP_003897.2	O60318-1
MCM3AP	XM_005261203.5 link	c.305C>T	p.Ser102Leu	missense_variant	2/29		XP_005261260.1	O60318-1
MCM3AP	XM_005261204.6 link	c.305C>T	p.Ser102Leu	missense_variant	2/29		XP_005261261.1	O60318-1
MCM3AP	XM_005261205.5 link	c.305C>T	p.Ser102Leu	missense_variant	2/29		XP_005261262.1	O60318-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MCM3AP	ENST00000291688.6 link	c.305C>T	p.Ser102Leu	missense_variant	1/28	1	NM_003906.5	ENSP00000291688.1	O60318-1
MCM3AP	ENST00000397708.1 link	c.305C>T	p.Ser102Leu	missense_variant	2/29	5		ENSP00000380820.1	O60318-1
MCM3AP	ENST00000426537.1 link	c.*23C>T		downstream_gene_variant		2		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

GnomAD3 exomes

AF:

0.319

AC:

80178

AN:

251278

Hom.:

13938

AF XY:

0.326

AC XY:

44323

AN XY:

135826

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 SAS exome

AF:

0.288

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

Gnomad4 AFR exome

AF:

0.210

Gnomad4 AMR exome

AF:

0.235

Gnomad4 ASJ exome

AF:

0.378

Gnomad4 EAS exome

AF:

0.112

Gnomad4 SAS exome

AF:

0.294

Gnomad4 FIN exome

AF:

0.306

Gnomad4 NFE exome

AF:

0.393

Gnomad4 OTH exome

AF:

0.348

GnomAD4 genome

AF:

0.313

AC:

47606

AN:

152146

Hom.:

8154

Cov.:

AF XY:

0.305

AC XY:

22703

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.375

Gnomad4 EAS

AF:

0.131

Gnomad4 SAS

AF:

0.276

Gnomad4 FIN

AF:

0.293

Gnomad4 NFE

AF:

0.395

Gnomad4 OTH

AF:

0.346

Alfa

AF:

0.377

Hom.:

13369

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 16574953) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

T;.

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.045

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.038

D;D

Polyphen

0.84

P;P

Vest4

0.38

MPC

0.16

ClinPred

0.029

GERP RS

4.6

Varity_R

0.15

gMVP

0.24

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