12-57755616-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138396.6(MARCHF9):​c.88C>T​(p.Pro30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,344,132 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 29)
Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

MARCHF9
NM_138396.6 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0064816773).
BS2
High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MARCHF9NM_138396.6 linkc.88C>T p.Pro30Ser missense_variant Exon 1 of 4 ENST00000266643.6 NP_612405.2
MARCHF9XM_047429894.1 linkc.88C>T p.Pro30Ser missense_variant Exon 1 of 3 XP_047285850.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MARCHF9ENST00000266643.6 linkc.88C>T p.Pro30Ser missense_variant Exon 1 of 4 1 NM_138396.6 ENSP00000266643.5 Q86YJ5-1
CDK4ENST00000552862.1 linkc.-20+316G>A intron_variant Intron 1 of 2 3 ENSP00000446763.1 F8W1L8
MARCHF9ENST00000552279.1 linkn.-112C>T upstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
151612
Hom.:
0
Cov.:
29
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:
0.00387
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00637
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000122
AC:
2
AN:
16336
Hom.:
0
AF XY:
0.000192
AC XY:
2
AN XY:
10428
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00490
Gnomad SAS exome
AF:
0.000253
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000132
AC:
157
AN:
1192414
Hom.:
2
Cov.:
31
AF XY:
0.000118
AC XY:
69
AN XY:
583392
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00471
Gnomad4 SAS exome
AF:
0.000101
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000102
Gnomad4 OTH exome
AF:
0.000272
GnomAD4 genome
AF:
0.000152
AC:
23
AN:
151718
Hom.:
0
Cov.:
29
AF XY:
0.000202
AC XY:
15
AN XY:
74124
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00388
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000306
ExAC
AF:
0.000158
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 12, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.88C>T (p.P30S) alteration is located in exon 1 (coding exon 1) of the MARCH9 gene. This alteration results from a C to T substitution at nucleotide position 88, causing the proline (P) at amino acid position 30 to be replaced by a serine (S). 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
0.077
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
16
DANN
Benign
0.85
DEOGEN2
Benign
0.029
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.52
T
MetaRNN
Benign
0.0065
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.014
Sift
Benign
0.63
T
Sift4G
Benign
0.33
T
Polyphen
0.043
B
Vest4
0.12
MutPred
0.30
Gain of catalytic residue at G33 (P = 0.0016);
MVP
0.055
MPC
1.1
ClinPred
0.024
T
GERP RS
1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.031
gMVP
0.25

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.

Other links and lift over

dbSNP: rs779553729; hg19: chr12-58149399; API