6-24781505-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015895.5(GMNN):c.158A>G(p.His53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,446,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: GMNN NM_015895.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0650

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06278965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMNN	NM_015895.5	c.158A>G	p.His53Arg	missense_variant	4/7	ENST00000230056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMNN	ENST00000230056.8	c.158A>G	p.His53Arg	missense_variant	4/7	1	NM_015895.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250638 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000968 AC: 14 AN: 1446022 Hom.: 0 Cov.: 25 AF XY: 0.0000111 AC XY: 8 AN XY: 719820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000909

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.158A>G (p.H53R) alteration is located in exon 4 (coding exon 3) of the GMNN gene. This alteration results from a A to G substitution at nucleotide position 158, causing the histidine (H) at amino acid position 53 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with GMNN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 53 of the GMNN protein (p.His53Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	2.2
Dann	Benign	0.64
DEOGEN2	Benign	0.078	T;T;.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.063	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M;M;.;M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.93	N;N;N;.;D;N
REVEL	Benign	0.023
Sift	Benign	0.12	T;T;T;.;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.;.
Vest4		0.090
MutPred		0.39		Loss of ubiquitination at K52 (P = 0.0161);Loss of ubiquitination at K52 (P = 0.0161);Loss of ubiquitination at K52 (P = 0.0161);Loss of ubiquitination at K52 (P = 0.0161);Loss of ubiquitination at K52 (P = 0.0161);Loss of ubiquitination at K52 (P = 0.0161);
MVP		0.42
MPC		0.38
ClinPred		0.055	T
GERP RS		-7.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.17

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: rs1053229509; hg19: chr6-24781733;