Genetic Variant MARCHF9:p.Cys134Gly (chr12-57756971-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138396.6(MARCHF9):c.400T>G(p.Cys134Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,599,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C134S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MARCHF9
NM_138396.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6 link	c.400T>G	p.Cys134Gly	missense_variant	Exon 2 of 4	ENST00000266643.6	NP_612405.2
MARCHF9	XM_047429894.1 link	c.400T>G	p.Cys134Gly	missense_variant	Exon 2 of 3		XP_047285850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF9	ENST00000266643.6 link	c.400T>G	p.Cys134Gly	missense_variant	Exon 2 of 4	1	NM_138396.6	ENSP00000266643.5		Q86YJ5-1
MARCHF9	ENST00000552279.1 link	n.201T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32920

American (AMR)

AF:

0.00

AC:

AN:

42912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25726

East Asian (EAS)

AF:

0.00

AC:

AN:

38754

South Asian (SAS)

AF:

0.00

AC:

AN:

83748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105494

Other (OTH)

AF:

0.00

AC:

AN:

59750

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

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.12

Eigen

Benign

0.030

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.71

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

8.0

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.30

Sift

Benign

0.21

Sift4G

Benign

0.30

Polyphen

0.010

Vest4

0.78

MutPred

0.73

Gain of catalytic residue at V132 (P = 9e-04);

MVP

0.50

MPC

1.4

ClinPred

0.96

GERP RS

5.0

Varity_R

0.70

gMVP

0.91

Mutation Taster

=36/64

disease causing

(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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12-57756971-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over