6-118827925-A-G

Variant names:

• chr6-118827925-A-G
• rs587777871
• NM_017696.3:c.1732+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_017696.3(MCM9):​c.1732+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MCM9 NM_017696.3 splice_donor, intron
• Scores: Splicing: ADA: 0.06253
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.95
• Publications: 7 publications found

Genes affected

MCM9 (HGNC:21484): (minichromosome maintenance 9 homologous recombination repair factor) The protein encoded by this gene is a member of the mini-chromosome maintenance (MCM) protein family that are essential for the initiation of eukaryotic genome replication. Binding of this protein to chromatin has been shown to be a pre-requisite for recruiting the MCM2-7 helicase to DNA replication origins. This protein also binds, and is a positive regulator of, the chromatin licensing and DNA replication factor 1, CDT1. [provided by RefSeq, Nov 2010]

MCM9 Gene-Disease associations (from GenCC):

• premature ovarian failure 10

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics
• 46,XX ovarian dysgenesis-short stature syndrome

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• male infertility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05944056 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-118827925-A-G is Pathogenic according to our data. Variant chr6-118827925-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 156587.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017696.3. 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
	MCM9	NM_017696.3	MANE Select	c.1732+2T>C		splice_donor intron	N/A	NP_060166.2
	MCM9	NM_001378356.1		c.1732+2T>C		splice_donor intron	N/A	NP_001365285.1
	MCM9	NM_001378357.1		c.1732+2T>C		splice_donor intron	N/A	NP_001365286.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM9	ENST00000619706.5	TSL:5 MANE Select	c.1732+2T>C		splice_donor intron	N/A	ENSP00000480469.1
	MCM9	ENST00000316316.10	TSL:5	c.1732+2T>C		splice_donor intron	N/A	ENSP00000314505.5
	MCM9	ENST00000458674.2	TSL:5	c.206-1061T>C		intron	N/A	ENSP00000406576.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000133 AC: 2 AN: 150126 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398442 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689754

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48280

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078926

Other (OTH) AF: 0.00 AC: 0 AN: 58086

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

46,XX ovarian dysgenesis-short stature syndrome Pathogenic:2

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice donor c.1732+2T>C variant in the MCM9 gene has been reported previously in homozygous state in an individual(s) affected with Premature ovarian failure (Wood-Trageser et al., 2014). Loss of function variants has been previously reported to be disease-causing. For the above-mentioned reasons, this variant has been classified as Pathogenic.

Dec 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Premature ovarian failure 1 Pathogenic:1

Rajkovic Lab, University of Pittsburgh

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.82
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		4.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.063
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 2

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

Other links and lift over

dbSNP: rs587777871; hg19: chr6-119149088;