rs779248881

Positions:

• chr21-46256907-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 0.727

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

ACMG classification

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: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}.
• 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/exons	MANE	UniProt
MCM3AP	NM_003906.5	c.3814G>A	p.Val1272Met	missense_variant	17/28	ENST00000291688.6
MCM3AP	XM_005261203.5	c.3814G>A	p.Val1272Met	missense_variant	18/29
MCM3AP	XM_005261204.6	c.3814G>A	p.Val1272Met	missense_variant	18/29
MCM3AP	XM_005261205.5	c.3814G>A	p.Val1272Met	missense_variant	18/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM3AP	ENST00000291688.6	c.3814G>A	p.Val1272Met	missense_variant	17/28	1	NM_003906.5	P1
MCM3AP-AS1	ENST00000590829.5	n.237-2017C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152270 Hom.: 0 Cov.: 34

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: 65 AN: 240314 Hom.: 0 AF XY: 0.000276 AC XY: 36 AN XY: 130432

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.: 0 Cov.: 36 AF XY: 0.000186 AC XY: 135 AN XY: 724606

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: 53 AN: 152270 Hom.: 0 Cov.: 34 AF XY: 0.000511 AC XY: 38 AN XY: 74394

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.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2018	- -
Uncertain significance, no assertion criteria provided	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 25, 2021	_x000D_ Criteria applied: PM3_VSTR, PP1_STR -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 09, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 05, 2022

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2022

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). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562048). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
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	N
LIST_S2	Benign	0.47	T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.70	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
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	T
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

Other links and lift over

dbSNP: rs779248881; hg19: chr21-47676821; COSMIC: COSV52437831; COSMIC: COSV52437831;