6-24780664-A-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.53A>C(p.Asn18Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0679 in 1,551,152 control chromosomes in the GnomAD database, including 12,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.089 (1601 hom., cov: 32)
  • Exomes 𝑓: 0.066 (11169 hom.)
• Consequence: GMNN NM_015895.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001447
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.107

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=1.1263939E-4).
• BP6: Variant 6-24780664-A-C is Benign according to our data. Variant chr6-24780664-A-C is described in ClinVar as [Benign]. Clinvar id is 1164494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMNN	NM_015895.5	c.53A>C	p.Asn18Thr	missense_variant, splice_region_variant	3/7	ENST00000230056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMNN	ENST00000230056.8	c.53A>C	p.Asn18Thr	missense_variant, splice_region_variant	3/7	1	NM_015895.5	P1

Frequencies

GnomAD3 genomes AF: 0.0891 AC: 13553 AN: 152114 Hom.: 1592 Cov.: 32

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0774

GnomAD3 exomes AF: 0.133 AC: 33408 AN: 250886 Hom.: 6104 AF XY: 0.119 AC XY: 16074 AN XY: 135638

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.542

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.0322

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0656 AC: 91720 AN: 1398922 Hom.: 11169 Cov.: 24 AF XY: 0.0647 AC XY: 45286 AN XY: 700042

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.550

Gnomad4 SAS exome AF: 0.0969

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0750

GnomAD4 genome AF: 0.0892 AC: 13576 AN: 152230 Hom.: 1601 Cov.: 32 AF XY: 0.0956 AC XY: 7116 AN XY: 74448

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0544 Hom.: 1582

Bravo AF: 0.106

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.0343 AC: 295

ExAC AF: 0.121 AC: 14654

Asia WGS AF: 0.270 AC: 938 AN: 3478

EpiCase AF: 0.0324

EpiControl AF: 0.0341

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

GMNN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	5.4
Dann	Benign	0.95
DEOGEN2	Benign	0.068	T;T;.;T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.48	N
MetaRNN	Benign	0.00011	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;M;.;.
MutationTaster	Benign	0.15	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N;N;N;.;N;N
REVEL	Benign	0.062
Sift	Benign	0.16	T;T;T;.;T;T
Sift4G	Benign	0.46	T;T;T;T;D;T
Polyphen		0.71	P;P;.;P;.;.
Vest4		0.076
MPC		0.32
ClinPred		0.042	T
GERP RS		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.010
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

LitVar

Other links and lift over

dbSNP: rs1923185; hg19: chr6-24780892; COSMIC: COSV57776868; COSMIC: COSV57776868;