rs2305952

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182746.3(MCM4):c.236-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,306 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 45 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 238 hom. )

Consequence

MCM4
NM_182746.3 splice_region, intron

Scores

Splicing: ADA: 0.003199

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.240

Publications

8 publications found

Variant links:

Genes affected

MCM4 (HGNC:6947): (minichromosome maintenance complex component 4) 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 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, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

MCM4 Gene-Disease associations (from GenCC):

primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

MCM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 8-47962049-A-G is Benign according to our data. Variant chr8-47962049-A-G is described in ClinVar as Benign. ClinVar VariationId is 363215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182746.3. 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
	MCM4	NM_182746.3	MANE Select	c.236-4A>G		splice_region intron	N/A	NP_877423.1	P33991
	MCM4	NM_005914.4		c.236-4A>G		splice_region intron	N/A	NP_005905.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCM4	ENST00000649973.1	MANE Select	c.236-4A>G		splice_region intron	N/A	ENSP00000496964.1	P33991
MCM4	ENST00000262105.6	TSL:1	c.236-4A>G		splice_region intron	N/A	ENSP00000262105.2	P33991
MCM4	ENST00000936718.1		c.256A>G	p.Ile86Val	missense	Exon 4 of 17	ENSP00000606777.1

Frequencies

GnomAD3 genomes

AF:

0.00478

AC:

727

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00994

AC:

2486

AN:

249976

AF XY:

0.00920

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.00428

GnomAD4 exome

AF:

0.00321

AC:

4696

AN:

1461016

Hom.:

238

Cov.:

AF XY:

0.00323

AC XY:

2344

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33448

American (AMR)

AF:

0.000292

AC:

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0976

AC:

3873

AN:

39694

South Asian (SAS)

AF:

0.00279

AC:

240

AN:

86030

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1111700

Other (OTH)

AF:

0.00714

AC:

431

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

258

517

775

1034

1292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00477

AC:

727

AN:

152290

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

400

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41552

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.126

AC:

650

AN:

5178

South Asian (SAS)

AF:

0.00683

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000701

Hom.:

Bravo

AF:

0.00542

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

4.4

(source)

DANN

Benign

0.80

PhyloP100

-0.24

BranchPoint Hunter

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0032

dbscSNV1_RF

Benign

0.28

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over