rs762679

Variant names:

• chr8-47972876-T-A
• rs762679
• NM_182746.3:c.1948T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-47972876-T-A
• chr8-47972876-T-C
• chr8-47972876-T-G

Variant summary

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

The NM_182746.3(MCM4):​c.1948T>A​(p.Leu650Met) variant causes a missense change. The variant allele was found at a frequency of 0.862 in 1,613,868 control chromosomes in the GnomAD database, including 600,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L650T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.88 (59487 hom., cov: 33)
  • Exomes 𝑓: 0.86 (541232 hom.)
• Consequence: MCM4 NM_182746.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.09
• Publications: 64 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.45541E-7).
• BP6: Variant 8-47972876-T-A is Benign according to our data. Variant chr8-47972876-T-A is described in ClinVar as Benign. ClinVar VariationId is 363238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.1948T>A	p.Leu650Met	missense	Exon 14 of 17	NP_877423.1
	MCM4	NM_005914.4		c.1948T>A	p.Leu650Met	missense	Exon 13 of 16	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000649973.1	MANE Select	c.1948T>A	p.Leu650Met	missense	Exon 14 of 17	ENSP00000496964.1
	MCM4	ENST00000262105.6	TSL:1	c.1948T>A	p.Leu650Met	missense	Exon 13 of 16	ENSP00000262105.2
	MCM4	ENST00000649838.1		c.2071T>A	p.Leu691Met	missense	Exon 15 of 18	ENSP00000497648.1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134338 AN: 152140 Hom.: 59422 Cov.: 33

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.930

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.868

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.889

GnomAD2 exomes AF: 0.872 AC: 219014 AN: 251290 AF XY: 0.867

Gnomad AFR exome AF: 0.926

Gnomad AMR exome AF: 0.928

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.835

Gnomad NFE exome AF: 0.843

Gnomad OTH exome AF: 0.855

GnomAD4 exome AF: 0.860 AC: 1256733 AN: 1461610 Hom.: 541232 Cov.: 45 AF XY: 0.860 AC XY: 625052 AN XY: 727120

African (AFR) AF: 0.926 AC: 31001 AN: 33472

American (AMR) AF: 0.925 AC: 41382 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 21472 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39672 AN: 39698

South Asian (SAS) AF: 0.854 AC: 73695 AN: 86252

European-Finnish (FIN) AF: 0.836 AC: 44623 AN: 53408

Middle Eastern (MID) AF: 0.846 AC: 4882 AN: 5768

European-Non Finnish (NFE) AF: 0.852 AC: 947609 AN: 1111776

Other (OTH) AF: 0.868 AC: 52397 AN: 60382

GnomAD4 genome AF: 0.883 AC: 134465 AN: 152258 Hom.: 59487 Cov.: 33 AF XY: 0.883 AC XY: 65737 AN XY: 74434

African (AFR) AF: 0.926 AC: 38459 AN: 41552

American (AMR) AF: 0.911 AC: 13949 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2929 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5173 AN: 5174

South Asian (SAS) AF: 0.868 AC: 4180 AN: 4816

European-Finnish (FIN) AF: 0.838 AC: 8890 AN: 10604

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57915 AN: 68018

Other (OTH) AF: 0.890 AC: 1880 AN: 2112

Alfa AF: 0.860 Hom.: 42497

Bravo AF: 0.891

TwinsUK AF: 0.843 AC: 3127

ALSPAC AF: 0.854 AC: 3291

ESP6500AA AF: 0.924 AC: 4069

ESP6500EA AF: 0.847 AC: 7285

ExAC AF: 0.867 AC: 105227

Asia WGS AF: 0.929 AC: 3232 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.37
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.040	N
PhyloP100		7.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.090
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.12
MPC		0.18
ClinPred		0.0071	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.29
Mutation Taster		=99/1	polymorphism (auto)

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: rs762679; hg19: chr8-48885436; COSMIC: COSV107254765; COSMIC: COSV107254765;