10-13171119-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018518.5(MCM10):c.205G>A(p.Asp69Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,614,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

MCM10 (HGNC:18043): (minichromosome maintenance 10 replication initiation factor) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre-RC) and it may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein can interact with MCM2 and MCM6, as well as with the origin recognition protein ORC2. It is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. Studies of a similar protein in Xenopus suggest that the chromatin binding of this protein at the onset of DNA replication is after pre-RC assembly and before origin unwinding. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0096485615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM10	NM_018518.5	c.205G>A	p.Asp69Asn	missense_variant	3/20	ENST00000378714.8
MCM10	NM_182751.3	c.205G>A	p.Asp69Asn	missense_variant	3/20
MCM10	XM_011519538.3	c.205G>A	p.Asp69Asn	missense_variant	3/20
MCM10	XM_047425437.1	c.205G>A	p.Asp69Asn	missense_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM10	ENST00000378714.8	c.205G>A	p.Asp69Asn	missense_variant	3/20	1	NM_018518.5	P4
MCM10	ENST00000484800.6	c.205G>A	p.Asp69Asn	missense_variant	3/20	1		A1
MCM10	ENST00000378694.1	c.205G>A	p.Asp69Asn	missense_variant	2/18	5
MCM10	ENST00000479669.5	c.-36G>A		5_prime_UTR_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251364 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135842

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727248

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74492

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000833 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.205G>A (p.D69N) alteration is located in exon 3 (coding exon 2) of the MCM10 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the aspartic acid (D) at amino acid position 69 to be replaced by an asparagine (N). 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	Benign	0.066
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.9
Dann	Benign	0.84
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.86	L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.68	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.034
MVP		0.16
MPC		0.098
ClinPred		0.0057	T
GERP RS		2.8
Varity_R		0.020
gMVP		0.014

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: rs146076863; hg19: chr10-13213119; COSMIC: COSV66333138;