Genetic Variant NM_005916.5:c.1667T>C (chr7-100095399-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005916.5(MCM7):c.1667T>C(p.Met556Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,613,404 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000088 ( 2 hom. )

Consequence

MCM7
NM_005916.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.58

Variant links:

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]

MCM7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM7	NM_005916.5 link	c.1667T>C	p.Met556Thr	missense_variant	Exon 12 of 15	ENST00000303887.10	NP_005907.3	P33993-1C6EMX8A0A0S2Z4A5
MCM7	NM_001278595.2 link	c.1139T>C	p.Met380Thr	missense_variant	Exon 11 of 14		NP_001265524.1	P33993-3C6EMX8
MCM7	NM_182776.3 link	c.1139T>C	p.Met380Thr	missense_variant	Exon 11 of 14		NP_877577.1	P33993-3
MCM7	XM_005250348.4 link	c.1346T>C	p.Met449Thr	missense_variant	Exon 12 of 15		XP_005250405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM7	ENST00000303887.10 link	c.1667T>C	p.Met556Thr	missense_variant	Exon 12 of 15	1	NM_005916.5	ENSP00000307288.5		P33993-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000925

AC:

AN:

248598

Hom.:

AF XY:

0.0000743

AC XY:

AN XY:

134522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.000177

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461050

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1667T>C (p.M556T) alteration is located in exon 12 (coding exon 12) of the MCM7 gene. This alteration results from a T to C substitution at nucleotide position 1667, causing the methionine (M) at amino acid position 556 to be replaced by a threonine (T). 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.0060

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.19

.;.;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;.;T

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

.;.;L

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

D;.;D

REVEL

Uncertain

0.31

Sift

Benign

0.73

T;.;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.16

.;.;B

Vest4

0.94

MVP

0.51

MPC

0.27

ClinPred

0.12

GERP RS

6.2

Varity_R

0.85

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over