10-13171247-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_018518.5(MCM10):c.333G>A(p.Thr111=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,609,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: MCM10 NM_018518.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76

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 Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-13171247-G-A is Benign according to our data. Variant chr10-13171247-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 709266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM10	NM_018518.5	c.333G>A	p.Thr111=	synonymous_variant	3/20	ENST00000378714.8
MCM10	NM_182751.3	c.333G>A	p.Thr111=	synonymous_variant	3/20
MCM10	XM_011519538.3	c.333G>A	p.Thr111=	synonymous_variant	3/20
MCM10	XM_047425437.1	c.333G>A	p.Thr111=	synonymous_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM10	ENST00000378714.8	c.333G>A	p.Thr111=	synonymous_variant	3/20	1	NM_018518.5	P4
MCM10	ENST00000484800.6	c.333G>A	p.Thr111=	synonymous_variant	3/20	1		A1
MCM10	ENST00000378694.1	c.333G>A	p.Thr111=	synonymous_variant	2/18	5
MCM10	ENST00000479669.5	c.93G>A	p.Thr31=	synonymous_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000414 AC: 102 AN: 246084 Hom.: 0 AF XY: 0.000405 AC XY: 54 AN XY: 133450

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.000713

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000805 AC: 1173 AN: 1457200 Hom.: 1 Cov.: 31 AF XY: 0.000758 AC XY: 549 AN XY: 724668

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.0000916

Gnomad4 ASJ exome AF: 0.000655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000984

Gnomad4 OTH exome AF: 0.000765

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74462

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.2
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142919178; hg19: chr10-13213247;