chr7-100094248-C-G

Position:

• chr7-100094248-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005916.5(MCM7):​c.1773G>C​(p.Glu591Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,204 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: MCM7 NM_005916.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.78

Genes affected

MCM7 (HGNC:6950): (minichromosome maintenance complex component 7) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 6 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. Cyclin D1-dependent kinase, CDK4, is found to associate with this protein, and may regulate the binding of this protein with the tumorsuppressor protein RB1/RB. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011098564).
• BP6: Variant 7-100094248-C-G is Benign according to our data. Variant chr7-100094248-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 774658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM7	NM_005916.5	c.1773G>C	p.Glu591Asp	missense_variant	13/15	ENST00000303887.10
MCM7	NM_001278595.2	c.1245G>C	p.Glu415Asp	missense_variant	12/14
MCM7	NM_182776.3	c.1245G>C	p.Glu415Asp	missense_variant	12/14
MCM7	XM_005250348.4	c.1452G>C	p.Glu484Asp	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM7	ENST00000303887.10	c.1773G>C	p.Glu591Asp	missense_variant	13/15	1	NM_005916.5	P1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00199 AC: 501 AN: 251480 Hom.: 1 AF XY: 0.00198 AC XY: 269 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00320 AC: 4684 AN: 1461890 Hom.: 8 Cov.: 32 AF XY: 0.00312 AC XY: 2269 AN XY: 727246

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74476

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00234

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

MCM7-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.045	.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.59	.;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.75	N;.;N
REVEL	Benign	0.21
Sift	Benign	0.54	T;.;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0080	.;.;B
Vest4		0.74
MutPred		0.53		.;.;Loss of catalytic residue at W593 (P = 0.0318);
MVP		0.22
MPC		0.14
ClinPred		0.0074	T
GERP RS		2.2
Varity_R		0.26
gMVP		0.44

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: rs149624106; hg19: chr7-99691871;