chr12-57755548-G-T

Variant names:

Variant summary

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

The NM_138396.6(MARCHF9):c.20G>T(p.Arg7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000469 in 1,279,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MARCHF9
NM_138396.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

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=0.29713053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6 link	c.20G>T	p.Arg7Leu	missense_variant	Exon 1 of 4	ENST00000266643.6	NP_612405.2
MARCHF9	XM_047429894.1 link	c.20G>T	p.Arg7Leu	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>T	p.Arg7Leu	missense_variant	Exon 1 of 4	1	NM_138396.6	ENSP00000266643.5	Q86YJ5-1
CDK4	ENST00000552862.1 link	c.-20+384C>A		intron_variant	Intron 1 of 2	3		ENSP00000446763.1	F8W1L8
MARCHF9	ENST00000552279.1 link	n.-180G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000714

AC:

AN:

140028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000267

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

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

68784

AF XY:

0.0000249

show subpopulations

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:

0.0000386

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000518

AC:

AN:

1139224

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

559168

show subpopulations

African (AFR)

AF:

0.0000443

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:

0.0000828

AC:

AN:

24162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2926

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

933998

Other (OTH)

AF:

0.0000233

AC:

AN:

42828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000714

AC:

AN:

140028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67582

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000267

AC:

AN:

37416

American (AMR)

AF:

0.00

AC:

AN:

13350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

4388

South Asian (SAS)

AF:

0.00

AC:

AN:

4260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65588

Other (OTH)

AF:

0.00

AC:

AN:

1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.20G>T (p.R7L) alteration is located in exon 1 (coding exon 1) of the MARCH9 gene. This alteration results from a G to T substitution at nucleotide position 20, causing the arginine (R) at amino acid position 7 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Benign

0.17

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.61

M_CAP

Benign

0.053

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

4.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.97

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Benign

0.10

Polyphen

0.98

Vest4

0.28

MutPred

0.33

Loss of MoRF binding (P = 0.0071);

MVP

0.30

MPC

2.5

ClinPred

0.81

GERP RS

2.2

PromoterAI

0.052

Neutral

(source)

Varity_R

0.37

gMVP

0.51

Mutation Taster

=62/38

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.

chr12-57755548-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over