chr2-216369866-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000273067.5(MARCHF4):​c.395G>T​(p.Ser132Ile) variant causes a missense change. 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: 32)

Consequence

MARCHF4
ENST00000273067.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.95
Variant links:
Genes affected
MARCHF4 (HGNC:29269): (membrane associated ring-CH-type finger 4) MARCH4 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. MARCH4 reduces surface accumulation of several membrane glycoproteins by directing them to the endosomal compartment (Bartee et al., 2004 [PubMed 14722266]).[supplied by OMIM, Apr 2010]

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ACMG classification

Classification made for transcript

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=0.29031983).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MARCHF4NM_020814.3 linkuse as main transcriptc.395G>T p.Ser132Ile missense_variant 1/4 ENST00000273067.5 NP_065865.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MARCHF4ENST00000273067.5 linkuse as main transcriptc.395G>T p.Ser132Ile missense_variant 1/41 NM_020814.3 ENSP00000273067 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsFeb 14, 2023The c.395G>T (p.S132I) alteration is located in exon 1 (coding exon 1) of the MARCH4 gene. This alteration results from a G to T substitution at nucleotide position 395, causing the serine (S) at amino acid position 132 to be replaced by an isoleucine (I). 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
0.21
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.047
T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.29
T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
0.81
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.13
Sift
Benign
0.084
T
Sift4G
Benign
0.26
T
Polyphen
0.99
D
Vest4
0.20
MutPred
0.30
Gain of solvent accessibility (P = 0.008);
MVP
0.69
MPC
1.5
ClinPred
0.83
D
GERP RS
5.8
Varity_R
0.24
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

hg19: chr2-217234589; API