22-35400484-G-T

Variant names:

• chr22-35400484-G-T
• NM_006739.4:c.46G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006739.4(MCM5):​c.46G>T​(p.Gly16Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.10

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4	c.46G>T	p.Gly16Trp	missense_variant	Exon 2 of 17	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.46G>T	p.Gly16Trp	missense_variant	Exon 2 of 18		XP_006724305.1
MCM5	XM_047441366.1	c.46G>T	p.Gly16Trp	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.46G>T	p.Gly16Trp	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 specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>T (p.G16W) alteration is located in exon 2 (coding exon 1) of the MCM5 gene. This alteration results from a G to T substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.055	T;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.82
MutPred		0.42		Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);
MVP		0.70
MPC		1.1
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-35796477;