dbSNP rs864309488: GMNN:p.Lys17Arg (chr6-24777296-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_015895.5(GMNN):c.50A>G(p.Lys17Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GMNN
NM_015895.5 missense, splice_region

Scores

Splicing: ADA: 0.9383

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.51

Variant links:

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]

GMNN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-24777296-A-G is Pathogenic according to our data. Variant chr6-24777296-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204001.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-24777296-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.14323276). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMNN	NM_015895.5 link	c.50A>G	p.Lys17Arg	missense_variant, splice_region_variant	Exon 2 of 7	ENST00000230056.8	NP_056979.1	O75496A0A024QZY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMNN	ENST00000230056.8 link	c.50A>G	p.Lys17Arg	missense_variant, splice_region_variant	Exon 2 of 7	1	NM_015895.5	ENSP00000230056.3		O75496

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1081742

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

551842

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Meier-Gorlin syndrome

Pathogenic:1

Jun 17, 2015

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Likely pathogenicity based on finding it once de novo in a 3-year-old female with Meier-Gorlin syndrome. -

Meier-Gorlin syndrome 6

Pathogenic:1

Dec 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

T;T;.;T;T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.76

.;.;T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M;.;M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

N;N;N;.;N;N

REVEL

Benign

0.067

Sift

Benign

0.19

T;T;T;.;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.83

P;P;.;P;.;.

Vest4

0.76

MutPred

0.33

Loss of methylation at K17 (P = 0.014);Loss of methylation at K17 (P = 0.014);Loss of methylation at K17 (P = 0.014);Loss of methylation at K17 (P = 0.014);Loss of methylation at K17 (P = 0.014);Loss of methylation at K17 (P = 0.014);

MVP

0.37

MPC

0.45

ClinPred

0.97

GERP RS

5.2

Varity_R

0.12

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Benign

0.70

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over