chr6-24777296-A-G

Variant names:

• chr6-24777296-A-G
• rs864309488
• NM_015895.5:c.50A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

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
• 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: Uncertain_significance. The variant received 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 VariationId is 204001.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14323276). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMNN	NM_015895.5	MANE Select	c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	NP_056979.1
	GMNN	NM_001251989.2		c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	NP_001238918.1
	GMNN	NM_001251990.2		c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	NP_001238919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMNN	ENST00000230056.8	TSL:1 MANE Select	c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	ENSP00000230056.3
	GMNN	ENST00000356509.7	TSL:2	c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	ENSP00000348902.3
	GMNN	ENST00000620958.4	TSL:3	c.50A>G	p.Lys17Arg	missense splice_region	Exon 2 of 7	ENSP00000477506.1

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

African (AFR) AF: 0.00 AC: 0 AN: 23376

American (AMR) AF: 0.00 AC: 0 AN: 30504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22242

East Asian (EAS) AF: 0.00 AC: 0 AN: 33660

South Asian (SAS) AF: 0.00 AC: 0 AN: 66806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 801664

Other (OTH) AF: 0.00 AC: 0 AN: 46880

GnomAD4 genome Cov.: 32

Alfa AF: 0.000227 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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 v4.9

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
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.067
Sift	Benign	0.19	T
Sift4G	Benign	0.10	T
Polyphen		0.83	P
Vest4		0.76
MutPred		0.33		Loss of methylation at K17 (P = 0.014)
MVP		0.37
MPC		0.45
ClinPred		0.97	D
GERP RS		5.2
PromoterAI		0.0044	Neutral
Varity_R		0.12
gMVP		0.28
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309488; hg19: chr6-24777524;