6-24781491-G-C

Variant summary

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

The NM_015895.5(GMNN):c.144G>C(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,596,746 control chromosomes in the GnomAD database, including 2,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.072 (1145 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1080 hom.)
• Consequence: GMNN NM_015895.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.273

Genes affected

GMNN (HGNC:17493): (geminin DNA replication inhibitor) This gene encodes a protein that plays a critical role in cell cycle regulation. The encoded protein inhibits DNA replication by binding to DNA replication factor Cdt1, preventing the incorporation of minichromosome maintenance proteins into the pre-replication complex. The encoded protein is expressed during the S and G2 phases of the cell cycle and is degraded by the anaphase-promoting complex during the metaphase-anaphase transition. Increased expression of this gene may play a role in several malignancies including colon, rectal and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and two pseudogenes of this gene are located on the short arm of chromosome 16. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004207343).
• BP6: Variant 6-24781491-G-C is Benign according to our data. Variant chr6-24781491-G-C is described in ClinVar as [Benign]. Clinvar id is 1165184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMNN	NM_015895.5	c.144G>C	p.Leu48Phe	missense_variant	4/7	ENST00000230056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMNN	ENST00000230056.8	c.144G>C	p.Leu48Phe	missense_variant	4/7	1	NM_015895.5	P1

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10897 AN: 152030 Hom.: 1138 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.0752

GnomAD3 exomes AF: 0.0274 AC: 6849 AN: 249596 Hom.: 453 AF XY: 0.0246 AC XY: 3327 AN XY: 134994

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0297

Gnomad SAS exome AF: 0.0389

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0138 AC: 19948 AN: 1444598 Hom.: 1080 Cov.: 25 AF XY: 0.0140 AC XY: 10063 AN XY: 718824

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.0399

Gnomad4 FIN exome AF: 0.000603

Gnomad4 NFE exome AF: 0.00413

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0718 AC: 10926 AN: 152148 Hom.: 1145 Cov.: 32 AF XY: 0.0699 AC XY: 5196 AN XY: 74384

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0374

Gnomad4 SAS AF: 0.0456

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.0820

Alfa AF: 0.0171 Hom.: 142

Bravo AF: 0.0829

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.220 AC: 969

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.0343 AC: 4159

Asia WGS AF: 0.0670 AC: 234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;.;T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0042	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;.;M;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N;.;N;N
REVEL	Benign	0.12
Sift	Benign	0.089	T;T;T;.;T;T
Sift4G	Benign	0.070	T;T;T;T;T;T
Polyphen		0.93	P;P;.;P;.;.
Vest4		0.062
MutPred		0.17		Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MPC		0.54
ClinPred		0.030	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.028
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2307307; hg19: chr6-24781719; COSMIC: COSV57776981; COSMIC: COSV57776981;