Genetic Variant MARCHF9:p.Arg7Pro (chr12-57755548-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_138396.6(MARCHF9):c.20G>C(p.Arg7Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000878 in 1,139,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R7L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

MARCHF9
NM_138396.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.79

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33065265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6 link	c.20G>C	p.Arg7Pro	missense_variant	Exon 1 of 4	ENST00000266643.6	NP_612405.2
MARCHF9	XM_047429894.1 link	c.20G>C	p.Arg7Pro	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.20G>C	p.Arg7Pro	missense_variant	Exon 1 of 4	1	NM_138396.6	ENSP00000266643.5	Q86YJ5-1
CDK4	ENST00000552862.1 link	c.-20+384C>G		intron_variant	Intron 1 of 2	3		ENSP00000446763.1	F8W1L8
MARCHF9	ENST00000552279.1 link	n.-180G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.78e-7

AC:

AN:

1139228

Hom.:

Cov.:

AF XY:

0.00000179

AC XY:

AN XY:

559170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22598

American (AMR)

AF:

0.00

AC:

AN:

18230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17064

East Asian (EAS)

AF:

0.00

AC:

AN:

19622

South Asian (SAS)

AF:

0.00

AC:

AN:

57796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2926

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

934000

Other (OTH)

AF:

0.00

AC:

AN:

42828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.56

M_CAP

Benign

0.052

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

4.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.33

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Benign

0.10

Polyphen

0.99

Vest4

0.33

MutPred

0.37

Loss of MoRF binding (P = 9e-04);

MVP

0.41

MPC

2.7

ClinPred

0.88

GERP RS

2.2

PromoterAI

0.15

Neutral

(source)

Varity_R

0.33

gMVP

0.57

Mutation Taster

=54/46

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over