chr7-100095391-T-G

Variant names:

• chr7-100095391-T-G
• rs1795569310
• NM_005916.5:c.1675A>C

Variant summary

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

The NM_005916.5(MCM7):​c.1675A>C​(p.Met559Leu) 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: 34)
  • Exomes 𝑓: 0.0037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCM7 NM_005916.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM7	NM_005916.5	c.1675A>C	p.Met559Leu	missense_variant	Exon 12 of 15	ENST00000303887.10	NP_005907.3
MCM7	NM_001278595.2	c.1147A>C	p.Met383Leu	missense_variant	Exon 11 of 14		NP_001265524.1
MCM7	NM_182776.3	c.1147A>C	p.Met383Leu	missense_variant	Exon 11 of 14		NP_877577.1
MCM7	XM_005250348.4	c.1354A>C	p.Met452Leu	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	c.1675A>C	p.Met559Leu	missense_variant	Exon 12 of 15	1	NM_005916.5	ENSP00000307288.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00373 AC: 5379 AN: 1443622 Hom.: 0 Cov.: 33 AF XY: 0.00345 AC XY: 2482 AN XY: 718614

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.000556

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00451

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1675A>C (p.M559L) alteration is located in exon 12 (coding exon 12) of the MCM7 gene. This alteration results from a A to C substitution at nucleotide position 1675, causing the methionine (M) at amino acid position 559 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.097	.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.074
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.025	.;.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.75
MutPred		0.69		.;.;Loss of MoRF binding (P = 0.0815);
MVP		0.37
MPC		0.13
ClinPred		0.82	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.63

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: rs1795569310; hg19: chr7-99693014;