12-57755589-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138396.6(MARCHF9):c.61G>C(p.Gly21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,399,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MARCHF9
NM_138396.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.666

Publications

0 publications found

Variant links:

Genes affected

MARCHF9 (HGNC:25139): (membrane associated ring-CH-type finger 9) MARCH9 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH enzymes add ubiquitin (see MIM 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH9 induces internalization of several membrane glycoproteins and directs them to the endosomal compartment (Bartee et al., 2004 [PubMed 14722266]; Hoer et al., 2007 [PubMed 17174307]).[supplied by OMIM, Apr 2010]

MARCHF9 links:

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

CDK4 Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

CDK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07314482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6 link	c.61G>C	p.Gly21Arg	missense_variant	Exon 1 of 4	ENST00000266643.6	NP_612405.2
MARCHF9	XM_047429894.1 link	c.61G>C	p.Gly21Arg	missense_variant	Exon 1 of 3		XP_047285850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MARCHF9	ENST00000266643.6 link	c.61G>C	p.Gly21Arg	missense_variant	Exon 1 of 4	1	NM_138396.6	ENSP00000266643.5	Q86YJ5-1
CDK4	ENST00000552862.1 link	c.-20+343C>G		intron_variant	Intron 1 of 2	3		ENSP00000446763.1	F8W1L8
MARCHF9	ENST00000552279.1 link	n.-139G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1248988

Hom.:

Cov.:

AF XY:

0.00000813

AC XY:

AN XY:

615058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25284

American (AMR)

AF:

0.00

AC:

AN:

19830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20612

East Asian (EAS)

AF:

0.00

AC:

AN:

27224

South Asian (SAS)

AF:

0.00

AC:

AN:

62610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3530

European-Non Finnish (NFE)

AF:

0.0000139

AC:

AN:

1006556

Other (OTH)

AF:

0.00

AC:

AN:

50350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150628

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73432

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41210

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67222

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0067

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

M_CAP

Benign

0.044

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.67

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.18

REVEL

Benign

0.053

Sift

Benign

0.31

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.11

MutPred

0.36

Gain of methylation at G21 (P = 0.0062);

MVP

0.20

MPC

1.7

ClinPred

0.065

GERP RS

2.4

PromoterAI

0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.26

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-57755589-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over