chr22-35400566-G-T

Position:

• chr22-35400566-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
MCM5	NM_006739.4	c.128G>T	p.Arg43Leu	missense_variant	2/17	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.128G>T	p.Arg43Leu	missense_variant	2/18		XP_006724305.1
MCM5	XM_047441366.1	c.128G>T	p.Arg43Leu	missense_variant	2/18		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9	c.128G>T	p.Arg43Leu	missense_variant	2/17	1	NM_006739.4	ENSP00000216122	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This variant is not present in population databases (gnomAD no frequency). 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). This variant has not been reported in the literature in individuals affected with MCM5-related conditions. 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). -

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;.;.
MutationTaster	Benign	1.0	D;D
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
Varity_R		0.83
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-35796559; COSMIC: COSV53348624;