7-100101546-A-T

Variant names:

• chr7-100101546-A-T
• rs1534310
• ENST00000343023.10:c.-252T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000343023.10(MCM7):​c.-252T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 802,682 control chromosomes in the GnomAD database, including 30,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5067 hom., cov: 33)
  • Exomes 𝑓: 0.27 (25554 hom.)
• Consequence: MCM7 ENST00000343023.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.224

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]

AP4M1 (HGNC:574): (adaptor related protein complex 4 subunit mu 1) This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-100101546-A-T is Benign according to our data. Variant chr7-100101546-A-T is described in ClinVar as [Benign]. Clinvar id is 680067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100101546-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM7	NM_005916.5	c.-252T>A		upstream_gene_variant		ENST00000303887.10	NP_005907.3
AP4M1	NM_004722.4	c.-169A>T		upstream_gene_variant		ENST00000359593.9	NP_004713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM7	ENST00000303887.10	c.-252T>A		upstream_gene_variant		1	NM_005916.5	ENSP00000307288.5
AP4M1	ENST00000359593.9	c.-169A>T		upstream_gene_variant		1	NM_004722.4	ENSP00000352603.4

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38019 AN: 152034 Hom.: 5063 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.274 AC: 178428 AN: 650528 Hom.: 25554 Cov.: 8 AF XY: 0.275 AC XY: 94657 AN XY: 344224

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.250 AC: 38037 AN: 152154 Hom.: 5067 Cov.: 33 AF XY: 0.252 AC XY: 18749 AN XY: 74388

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.232

Alfa AF: 0.162 Hom.: 357

Bravo AF: 0.239

Asia WGS AF: 0.372 AC: 1295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.2
DANN	Benign	0.86

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: rs1534310; hg19: chr7-99699169;