rs864309488

Positions:

• chr6-24777296-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000230056.8(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 ENST00000230056.8 missense, splice_region
• Scores: Splicing: ADA: 0.9383
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.51

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 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/exons	MANE	Protein	UniProt
GMNN	NM_015895.5	c.50A>G	p.Lys17Arg	missense_variant, splice_region_variant	2/7	ENST00000230056.8	NP_056979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMNN	ENST00000230056.8	c.50A>G	p.Lys17Arg	missense_variant, splice_region_variant	2/7	1	NM_015895.5	ENSP00000230056	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1081742 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meier-Gorlin syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Baylor Genetics

Jun 17, 2015

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	27
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	D
LIST_S2	Benign	0.76	.;.;T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.50	T
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	D
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

Other links and lift over

dbSNP: rs864309488; hg19: chr6-24777524;