19-8421845-C-T

Variant names:

• chr19-8421845-C-T
• rs770136392
• NM_001005415.2:c.5C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001005415.2(MARCHF2):​c.5C>T​(p.Thr2Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,606,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MARCHF2 NM_001005415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

Genes affected

MARCHF2 (HGNC:28038): (membrane associated ring-CH-type finger 2) MARCH2 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. MARCH2 reduces surface accumulation of several glycoproteins and appears to regulate early endosome-to-trans-Golgi network (TGN) trafficking (Bartee et al., 2004 [PubMed 14722266]; Nakamura et al., 2005 [PubMed 15689499]).[supplied by OMIM, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29668826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF2	NM_001005415.2	c.5C>T	p.Thr2Met	missense_variant	Exon 2 of 5	ENST00000215555.7	NP_001005415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF2	ENST00000215555.7	c.5C>T	p.Thr2Met	missense_variant	Exon 2 of 5	5	NM_001005415.2	ENSP00000215555.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000369 AC: 9 AN: 243970 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 131988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.0000678

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1454524 Hom.: 0 Cov.: 30 AF XY: 0.0000221 AC XY: 16 AN XY: 723136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000433

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.0000832

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74346

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000453

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.T2M) alteration is located in exon 3 (coding exon 1) of the MARCH2 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the threonine (T) at amino acid position 2 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	Benign	0.25
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.013	.;.;.;T;.;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;.
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;M;.;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N;.;.;N;.;.;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.;.;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.62	P;.;.;D;.;.;D
Vest4		0.74
MutPred		0.27		Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);Loss of catalytic residue at T2 (P = 0.001);
MVP		0.36
MPC		1.0
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.60

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: rs770136392; hg19: chr19-8486729;