chr7-100095391-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M559R) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005916.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM7	NM_005916.5	MANE Select	c.1675A>C	p.Met559Leu	missense	Exon 12 of 15	NP_005907.3
	MCM7	NM_001439271.1		c.1354A>C	p.Met452Leu	missense	Exon 12 of 15	NP_001426200.1
	MCM7	NM_001439272.1		c.1354A>C	p.Met452Leu	missense	Exon 12 of 15	NP_001426201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM7	ENST00000303887.10	TSL:1 MANE Select	c.1675A>C	p.Met559Leu	missense	Exon 12 of 15	ENSP00000307288.5	P33993-1
	MCM7	ENST00000343023.10	TSL:1	c.986-2275A>C		intron	N/A	ENSP00000344006.6	P33993-2
	MCM7	ENST00000489841.6	TSL:1	n.2396A>C		non_coding_transcript_exon	Exon 11 of 14

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00311 AC: 103 AN: 33124

American (AMR) AF: 0.000270 AC: 12 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 25984

East Asian (EAS) AF: 0.000556 AC: 22 AN: 39578

South Asian (SAS) AF: 0.00128 AC: 109 AN: 85462

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.00230 AC: 13 AN: 5640

European-Non Finnish (NFE) AF: 0.00451 AC: 4946 AN: 1096300

Other (OTH) AF: 0.00244 AC: 146 AN: 59770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.025	N
PhyloP100		7.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs1795569310; hg19: chr7-99693014;