21-46256907-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_003906.5(MCM3AP):c.3814G>A(p.Val1272Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,609,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

MCM3AP
NM_003906.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 0.727

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:

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

MCM3AP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-46256907-C-T is Pathogenic according to our data. Variant chr21-46256907-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 562048.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.004172921). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM3AP	NM_003906.5 link	c.3814G>A	p.Val1272Met	missense_variant	Exon 17 of 28	ENST00000291688.6	NP_003897.2	O60318-1
MCM3AP	XM_005261203.5 link	c.3814G>A	p.Val1272Met	missense_variant	Exon 18 of 29		XP_005261260.1	O60318-1
MCM3AP	XM_005261204.6 link	c.3814G>A	p.Val1272Met	missense_variant	Exon 18 of 29		XP_005261261.1	O60318-1
MCM3AP	XM_005261205.5 link	c.3814G>A	p.Val1272Met	missense_variant	Exon 18 of 29		XP_005261262.1	O60318-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM3AP	ENST00000291688.6 link	c.3814G>A	p.Val1272Met	missense_variant	Exon 17 of 28	1	NM_003906.5	ENSP00000291688.1		O60318-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00357

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000270

AC:

AN:

240314

Hom.:

AF XY:

0.000276

AC XY:

AN XY:

130432

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00253

Gnomad NFE exome

AF:

0.000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

268

AN:

1457516

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

724606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00179

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000348

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00357

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development

Pathogenic:3Uncertain:1

Nov 25, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PM3_VSTR, PP1_STR -

Jun 09, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Sep 21, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 16, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

The heterozygous p.Val1272Met variant in MCM3AP was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 2 siblings with peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (PMID: 32202298). The variant has also been reported in 3 Finnish individuals with peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (PMID: 28633435), segregated with disease in 3 affected relatives from 2 families (PMID: 28633435, 32202298), and has been identified in 0.25% (60/24060) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779248881). This variant has been seen in the general population, in a heterozygous state, at greater rate than expected for disorder. This variant has also been reported in ClinVar (Variation ID: 562048) as pathogenic by OMIM. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 28633435, 32202298). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein. In summary, the clinical significance of the variant is uncertain. ACMG/AMP Criteria applied: PP1_moderate, BP4, PS3_moderate, BS1 (Richards 2015). -

not provided

Pathogenic:1

Oct 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1272 of the MCM3AP protein (p.Val1272Met). This variant is present in population databases (rs779248881, gnomAD 0.3%). This missense change has been observed in individual(s) with MCM3AP-related conditions (PMID: 28633435, 32202298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562048). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters MCM3AP gene expression (PMID: 28633435, 32202298). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Oct 05, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MCM3AP c.3814G>A (p.Val1272Met) results in a conservative amino acid change located in the germinal-centre associated nuclear protein, MCM3AP domain (IPR031907) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 240314 control chromosomes, predominantly within the Finnish population of the gnomAD database at a frequency of 0.0025. The variant, c.3814G>A, has been reported in the literature as a compound heterozygous genotype in three siblings with peripheral neuropathy from a Finnish family where it segregated with the disease phenotype and was also reported in an Estonian family in two siblings affected with polyneuropathy and progressive encephalopathy (e.g. Ylikallio_2017, Woldegebrie_2020). Experimental studies using fibroblasts derived from individuals from each of these two families suggest that the variant may reduce mRNA and protein expression, however since the variant of interest was assessed together with the other variants present in these patients, the impact ascribed to this particular variant is difficult to determine (e.g. Ylikallio_2017, Woldegebrie_2020). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three classified the variant as either pathogenic (n=2) or likely pathogenic (n=1), and two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.0

DANN

Benign

0.94

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.47

T;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.70

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.082

Sift

Benign

0.18

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.042

B;B

Vest4

0.064

MVP

0.24

MPC

0.13

ClinPred

0.032

GERP RS

0.0053

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.2

Varity_R

0.021

gMVP

0.19

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