12-57758246-C-G

Variant names:

• chr12-57758246-C-G
• NM_138396.6:c.652C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138396.6(MARCHF9):​c.652C>G​(p.Leu218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MARCHF9 NM_138396.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

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]

ACMG classification

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=0.39195147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6	c.652C>G	p.Leu218Val	missense_variant	Exon 3 of 4	ENST00000266643.6	NP_612405.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF9	ENST00000266643.6	c.652C>G	p.Leu218Val	missense_variant	Exon 3 of 4	1	NM_138396.6	ENSP00000266643.5
MARCHF9	ENST00000548358.1	c.313C>G	p.Leu105Val	missense_variant	Exon 1 of 2	1		ENSP00000446758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.652C>G (p.L218V) alteration is located in exon 3 (coding exon 3) of the MARCH9 gene. This alteration results from a C to G substitution at nucleotide position 652, causing the leucine (L) at amino acid position 218 to be replaced by a valine (V). 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	0.27
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.92	L;.
PhyloP100		2.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.40		Gain of catalytic residue at L219 (P = 0.0098);.;
MVP		0.68
MPC		0.62
ClinPred		0.69	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.86
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

hg19: chr12-58152029;