Variant 4-163700851-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394959.1(MARCHF1):c.124C>T(p.Pro42Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,383,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MARCHF1
NM_001394959.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

Genes affected

MARCHF1 (HGNC:26077): (membrane associated ring-CH-type finger 1) MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH proteins add ubiquitin (see MIM 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH1 downregulates the surface expression of major histocompatibility complex (MHC) class II molecules (see MIM 142880) and other glycoproteins by directing them to the late endosomal/lysosomal compartment (Bartee et al., 2004 [PubMed 14722266]; Thibodeau et al., 2008 [PubMed 18389477]; De Gassart et al., 2008 [PubMed 18305173]).[supplied by OMIM, Mar 2010]

MARCHF1 links:

MARCHF1 (HGNC:):

MARCHF1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13876367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCHF1	NM_001394959.1 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	5/10	ENST00000514618.6	NP_001381888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCHF1	ENST00000514618.6 linkuse as main transcript	c.124C>T	p.Pro42Ser	missense_variant	5/10	5	NM_001394959.1	ENSP00000421322.1		D6RGC4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000694

AC:

AN:

144024

Hom.:

AF XY:

0.00

AC XY:

AN XY:

76900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1383854

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682882

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:

0.00000186

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

Sep 02, 2024

The c.124C>T (p.P42S) alteration is located in exon 4 (coding exon 2) of the MARCH1 gene. This alteration results from a C to T substitution at nucleotide position 124, causing the proline (P) at amino acid position 42 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

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.042

T;T;.;.

Eigen

Benign

0.046

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.84

N;N;N;N

REVEL

Benign

0.030

Sift

Benign

0.34

T;T;D;T

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.52

P;P;.;.

Vest4

0.24

MutPred

0.22

Gain of glycosylation at S47 (P = 0.0064);Gain of glycosylation at S47 (P = 0.0064);Gain of glycosylation at S47 (P = 0.0064);Gain of glycosylation at S47 (P = 0.0064);

MVP

0.47

MPC

0.67

ClinPred

0.39

GERP RS

4.6

Varity_R

0.079

gMVP

0.68

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over