6-24781507-C-T

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.160C>T(p.Arg54Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,592,666 control chromosomes in the GnomAD database, including 2,242 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 (1146 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1096 hom.)
• Consequence: GMNN NM_015895.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.276

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=0.0010660589).
• BP6: Variant 6-24781507-C-T is Benign according to our data. Variant chr6-24781507-C-T is described in ClinVar as [Benign]. Clinvar id is 1165185.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.160C>T	p.Arg54Trp	missense_variant	4/7	ENST00000230056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMNN	ENST00000230056.8	c.160C>T	p.Arg54Trp	missense_variant	4/7	1	NM_015895.5	P1

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10898 AN: 151944 Hom.: 1139 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.0751

GnomAD3 exomes AF: 0.0276 AC: 6879 AN: 249466 Hom.: 459 AF XY: 0.0247 AC XY: 3337 AN XY: 134886

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0139 AC: 20076 AN: 1440604 Hom.: 1096 Cov.: 25 AF XY: 0.0141 AC XY: 10134 AN XY: 717212

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.000586

Gnomad4 NFE exome AF: 0.00415

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0719 AC: 10927 AN: 152062 Hom.: 1146 Cov.: 32 AF XY: 0.0699 AC XY: 5195 AN XY: 74340

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.0459

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.0227 Hom.: 481

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: 4161

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	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.086
DEOGEN2	Benign	0.050	T;T;.;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
MetaRNN	Benign	0.0011	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;.;N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	4.4	N;N;N;.;N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;.
Vest4		0.037
MPC		0.13
ClinPred		0.0023	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2307306; hg19: chr6-24781735; COSMIC: COSV57776988; COSMIC: COSV57776988;