22-35400659-C-G

Variant names:

• chr22-35400659-C-G
• rs743813
• NM_006739.4:c.167+54C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006739.4(MCM5):​c.167+54C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,502,800 control chromosomes in the GnomAD database, including 187,687 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (14304 hom., cov: 32)
  • Exomes 𝑓: 0.50 (173383 hom.)
• Consequence: MCM5 NM_006739.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34
• Publications: 12 publications found

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

MCM5 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4	c.167+54C>G		intron_variant	Intron 2 of 16	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.167+54C>G		intron_variant	Intron 2 of 17		XP_006724305.1
MCM5	XM_047441366.1	c.167+54C>G		intron_variant	Intron 2 of 17		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9	c.167+54C>G		intron_variant	Intron 2 of 16	1	NM_006739.4	ENSP00000216122.3

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59219 AN: 151822 Hom.: 14302 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.412

GnomAD4 exome AF: 0.497 AC: 671988 AN: 1350860 Hom.: 173383 AF XY: 0.495 AC XY: 327736 AN XY: 661974

African (AFR) AF: 0.0989 AC: 3056 AN: 30914

American (AMR) AF: 0.440 AC: 14717 AN: 33484

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 10733 AN: 21740

East Asian (EAS) AF: 0.186 AC: 6697 AN: 36074

South Asian (SAS) AF: 0.366 AC: 26481 AN: 72294

European-Finnish (FIN) AF: 0.555 AC: 21684 AN: 39100

Middle Eastern (MID) AF: 0.493 AC: 1945 AN: 3948

European-Non Finnish (NFE) AF: 0.531 AC: 560942 AN: 1057194

Other (OTH) AF: 0.459 AC: 25733 AN: 56112

GnomAD4 genome AF: 0.390 AC: 59232 AN: 151940 Hom.: 14304 Cov.: 32 AF XY: 0.389 AC XY: 28895 AN XY: 74226

African (AFR) AF: 0.109 AC: 4544 AN: 41504

American (AMR) AF: 0.470 AC: 7176 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1809 AN: 3468

East Asian (EAS) AF: 0.145 AC: 746 AN: 5162

South Asian (SAS) AF: 0.352 AC: 1691 AN: 4802

European-Finnish (FIN) AF: 0.543 AC: 5703 AN: 10510

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36062 AN: 67924

Other (OTH) AF: 0.411 AC: 868 AN: 2110

Alfa AF: 0.452 Hom.: 2106

Bravo AF: 0.370

Asia WGS AF: 0.228 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.42
PhyloP100		2.3
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	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: rs743813; hg19: chr22-35796652; COSMIC: COSV53347230;