22-35400566-G-T

Variant names:

• chr22-35400566-G-T
• rs2145779463
• NM_006739.4:c.128G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006739.4(MCM5):​c.128G>T​(p.Arg43Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCM5 NM_006739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50
• Publications: 0 publications found

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

MCM5 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4	c.128G>T	p.Arg43Leu	missense_variant	Exon 2 of 17	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.128G>T	p.Arg43Leu	missense_variant	Exon 2 of 18		XP_006724305.1
MCM5	XM_047441366.1	c.128G>T	p.Arg43Leu	missense_variant	Exon 2 of 18		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9	c.128G>T	p.Arg43Leu	missense_variant	Exon 2 of 17	1	NM_006739.4	ENSP00000216122.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 43 of the MCM5 protein (p.Arg43Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1406715). This variant has not been reported in the literature in individuals affected with MCM5-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D;D;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		0.36	B;B;.
Vest4		0.93
MutPred		0.52		Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);
MVP		0.78
MPC		0.53
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.0026	Neutral
Varity_R		0.83
gMVP		0.81
Mutation Taster		=41/59	disease causing

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: rs2145779463; hg19: chr22-35796559; COSMIC: COSV53348624;