Variant chr19-8430658-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001005415.2(MARCHF2):c.373T>C(p.Trp125Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MARCHF2
NM_001005415.2 missense, splice_region

Scores

Splicing: ADA: 0.2857

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.94

Variant links:

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]

MARCHF2 links:

MARCHF2 (HGNC:):

MARCHF2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCHF2	NM_001005415.2 linkuse as main transcript	c.373T>C	p.Trp125Arg	missense_variant, splice_region_variant	4/5	ENST00000215555.7	NP_001005415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCHF2	ENST00000215555.7 linkuse as main transcript	c.373T>C	p.Trp125Arg	missense_variant, splice_region_variant	4/5	5	NM_001005415.2	ENSP00000215555.2		Q9P0N8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454568

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.373T>C (p.W125R) alteration is located in exon 5 (coding exon 3) of the MARCH2 gene. This alteration results from a T to C substitution at nucleotide position 373, causing the tryptophan (W) at amino acid position 125 to be replaced by an arginine (R). 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

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-10

D;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.44

Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);

MVP

0.63

MPC

1.4

ClinPred

1.0

GERP RS

4.9

Varity_R

0.88

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.29

dbscSNV1_RF

Benign

0.48

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over