12-57756975-C-T

Variant names:

• chr12-57756975-C-T
• rs1013662037
• NM_138396.6:c.404C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138396.6(MARCHF9):​c.404C>T​(p.Thr135Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,446,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MARCHF9 NM_138396.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF9	NM_138396.6	c.404C>T	p.Thr135Met	missense_variant	Exon 2 of 4	ENST00000266643.6	NP_612405.2
MARCHF9	XM_047429894.1	c.404C>T	p.Thr135Met	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	c.404C>T	p.Thr135Met	missense_variant	Exon 2 of 4	1	NM_138396.6	ENSP00000266643.5
MARCHF9	ENST00000552279.1	n.205C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000446 AC: 1 AN: 224030 Hom.: 0 AF XY: 0.00000821 AC XY: 1 AN XY: 121744

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 SAS exome AF: 0.0000362

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446840 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 718780

Gnomad4 AFR exome AF: 0.0000607

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404C>T (p.T135M) alteration is located in exon 2 (coding exon 2) of the MARCH9 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the threonine (T) at amino acid position 135 to be replaced by a methionine (M). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.55		Gain of catalytic residue at V132 (P = 4e-04);
MVP		0.79
MPC		2.3
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.88

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

Other links and lift over

dbSNP: rs1013662037; hg19: chr12-58150758;