rs864309486

Variant names:

• chr6-24777262-A-T
• rs864309486
• NM_015895.5:c.16A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_015895.5(GMNN):​c.16A>T​(p.Lys6*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GMNN NM_015895.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.51
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.975 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-24777262-A-T is Pathogenic according to our data. Variant chr6-24777262-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 203999.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015895.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMNN	NM_015895.5	MANE Select	c.16A>T	p.Lys6*	stop_gained	Exon 2 of 7	NP_056979.1
	GMNN	NM_001251989.2		c.16A>T	p.Lys6*	stop_gained	Exon 2 of 7	NP_001238918.1
	GMNN	NM_001251990.2		c.16A>T	p.Lys6*	stop_gained	Exon 2 of 7	NP_001238919.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMNN	ENST00000230056.8	TSL:1 MANE Select	c.16A>T	p.Lys6*	stop_gained	Exon 2 of 7	ENSP00000230056.3
	GMNN	ENST00000931913.1		c.16A>T	p.Lys6*	stop_gained	Exon 2 of 8	ENSP00000601972.1
	GMNN	ENST00000356509.7	TSL:2	c.16A>T	p.Lys6*	stop_gained	Exon 2 of 7	ENSP00000348902.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1261074 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 635082

African (AFR) AF: 0.00 AC: 0 AN: 27324

American (AMR) AF: 0.00 AC: 0 AN: 33088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23640

East Asian (EAS) AF: 0.00 AC: 0 AN: 35394

South Asian (SAS) AF: 0.00 AC: 0 AN: 72942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957802

Other (OTH) AF: 0.00 AC: 0 AN: 53150

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meier-Gorlin syndrome (1)
1	-	-	Meier-Gorlin syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		4.5
Vest4		0.69
GERP RS		5.1
PromoterAI		0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 35

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

Other links and lift over

dbSNP: rs864309486; hg19: chr6-24777490;