NM_003906.5:c.305C>T

Variant names:

• chr21-46284982-G-A
• rs9975588
• NM_003906.5:c.305C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.82
• Publications: 45 publications found

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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM3AP	NM_003906.5	c.305C>T	p.Ser102Leu	missense_variant	Exon 1 of 28	ENST00000291688.6	NP_003897.2
MCM3AP	XM_005261203.5	c.305C>T	p.Ser102Leu	missense_variant	Exon 2 of 29		XP_005261260.1
MCM3AP	XM_005261204.6	c.305C>T	p.Ser102Leu	missense_variant	Exon 2 of 29		XP_005261261.1
MCM3AP	XM_005261205.5	c.305C>T	p.Ser102Leu	missense_variant	Exon 2 of 29		XP_005261262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM3AP	ENST00000291688.6	c.305C>T	p.Ser102Leu	missense_variant	Exon 1 of 28	1	NM_003906.5	ENSP00000291688.1
MCM3AP	ENST00000397708.1	c.305C>T	p.Ser102Leu	missense_variant	Exon 2 of 29	5		ENSP00000380820.1
MCM3AP	ENST00000426537.1	c.*23C>T		downstream_gene_variant		2		ENSP00000408934.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47592 AN: 152028 Hom.: 8156 Cov.: 33

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

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.: 54 AF XY: 0.365 AC XY: 265292 AN XY: 727166

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

GnomAD4 genome AF: 0.313 AC: 47606 AN: 152146 Hom.: 8154 Cov.: 33 AF XY: 0.305 AC XY: 22703 AN XY: 74388

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

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16574953) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;.
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		4.8
PrimateAI	Benign	0.45	T
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	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.24
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9975588; hg19: chr21-47704896; COSMIC: COSV52438168; COSMIC: COSV52438168;