6-118814839-C-T

Position:

chr6-118814839-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_017696.3(MCM9):c.3417G>A(p.Met1139Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,497,636 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

MCM9
NM_017696.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.405

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036869347).

BP6

Variant 6-118814839-C-T is Benign according to our data. Variant chr6-118814839-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2656888.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM9	NM_017696.3 linkuse as main transcript	c.3417G>A	p.Met1139Ile	missense_variant	14/14	ENST00000619706.5	NP_060166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM9	ENST00000619706.5 linkuse as main transcript	c.3417G>A	p.Met1139Ile	missense_variant	14/14	5	NM_017696.3	ENSP00000480469	P1	Q9NXL9-1
MCM9	ENST00000316316.10 linkuse as main transcript	c.3417G>A	p.Met1139Ile	missense_variant	13/13	5		ENSP00000314505	P1	Q9NXL9-1

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00943

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000681

AC:

AN:

110130

Hom.:

AF XY:

0.000600

AC XY:

AN XY:

58380

show subpopulations

Gnomad AFR exome

AF:

0.00993

Gnomad AMR exome

AF:

0.000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000250

AC:

337

AN:

1345516

Hom.:

Cov.:

AF XY:

0.000225

AC XY:

148

AN XY:

658772

show subpopulations

Gnomad4 AFR exome

AF:

0.00801

Gnomad4 AMR exome

AF:

0.000538

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:

0.0000455

Gnomad4 OTH exome

AF:

0.000702

GnomAD4 genome

AF:

0.00273

AC:

415

AN:

152120

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00940

Gnomad4 AMR

AF:

0.000852

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00314

ExAC

AF:

0.000585

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.3417G>A (p.M1139I) alteration is located in exon 12 (coding exon 12) of the MCM9 gene. This alteration results from a G to A substitution at nucleotide position 3417, causing the methionine (M) at amino acid position 1139 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

MCM9: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.65

.;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.70

N;.

REVEL

Benign

0.058

Sift

Benign

0.22

T;.

Sift4G

Benign

0.55

T;T

Polyphen

0.0060

B;B

Vest4

0.18

MutPred

0.29

Gain of catalytic residue at M1139 (P = 0.0364);Gain of catalytic residue at M1139 (P = 0.0364);

MVP

0.20

MPC

0.13

ClinPred

0.011

GERP RS

2.2

Varity_R

0.072

gMVP

0.083

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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