rs1122598

Variant names:

• chr7-100101813-G-A
• rs1122598
• ENST00000343023.10:c.-519C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100101813-G-A
• chr7-100101813-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000343023.10(MCM7):​c.-519C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,607,650 control chromosomes in the GnomAD database, including 29,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2695 hom., cov: 33)
  • Exomes 𝑓: 0.18 (27141 hom.)
• Consequence: MCM7 ENST00000343023.10 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.154
• Publications: 15 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]

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]

AP4M1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 50

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-100101813-G-A is Benign according to our data. Variant chr7-100101813-G-A is described in ClinVar as [Benign]. Clinvar id is 1268357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4	c.58+41G>A		intron_variant	Intron 1 of 14	ENST00000359593.9	NP_004713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9	c.58+41G>A		intron_variant	Intron 1 of 14	1	NM_004722.4	ENSP00000352603.4

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23887 AN: 152000 Hom.: 2695 Cov.: 33

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.219 AC: 53213 AN: 242780 AF XY: 0.215

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.403

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.181 AC: 263719 AN: 1455538 Hom.: 27141 Cov.: 34 AF XY: 0.183 AC XY: 132908 AN XY: 724362

African (AFR) AF: 0.0312 AC: 1041 AN: 33358

American (AMR) AF: 0.352 AC: 15720 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7063 AN: 26090

East Asian (EAS) AF: 0.407 AC: 16148 AN: 39636

South Asian (SAS) AF: 0.228 AC: 19595 AN: 86112

European-Finnish (FIN) AF: 0.171 AC: 8910 AN: 52144

Middle Eastern (MID) AF: 0.357 AC: 1968 AN: 5506

European-Non Finnish (NFE) AF: 0.164 AC: 181350 AN: 1107974

Other (OTH) AF: 0.198 AC: 11924 AN: 60100

GnomAD4 genome AF: 0.157 AC: 23889 AN: 152112 Hom.: 2695 Cov.: 33 AF XY: 0.164 AC XY: 12184 AN XY: 74346

African (AFR) AF: 0.0356 AC: 1478 AN: 41538

American (AMR) AF: 0.295 AC: 4510 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 975 AN: 3468

East Asian (EAS) AF: 0.375 AC: 1928 AN: 5136

South Asian (SAS) AF: 0.230 AC: 1109 AN: 4826

European-Finnish (FIN) AF: 0.175 AC: 1848 AN: 10580

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11386 AN: 67970

Other (OTH) AF: 0.189 AC: 400 AN: 2114

Alfa AF: 0.122 Hom.: 309

Bravo AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		0.15
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=125/175	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1122598; hg19: chr7-99699436; COSMIC: COSV57993817; COSMIC: COSV57993817;