4-163585902-C-G

Position:

• chr4-163585902-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394959.1(MARCHF1):​c.1038G>C​(p.Glu346Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARCHF1 NM_001394959.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.510

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]

ACMG classification

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=0.13229474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCHF1	NM_001394959.1	c.1038G>C	p.Glu346Asp	missense_variant	8/10	ENST00000514618.6	NP_001381888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCHF1	ENST00000514618.6	c.1038G>C	p.Glu346Asp	missense_variant	8/10	5	NM_001394959.1	ENSP00000421322

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.270G>C (p.E90D) alteration is located in exon 6 (coding exon 4) of the MARCH1 gene. This alteration results from a G to C substitution at nucleotide position 270, causing the glutamic acid (E) at amino acid position 90 to be replaced by an aspartic acid (D). 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	0.060
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;T;.;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;.;.;.
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.58	N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.67	T;T;T;T;T
Polyphen		0.024	B;B;.;B;.
Vest4		0.21
MutPred		0.32		Gain of glycosylation at T95 (P = 0.0235);Gain of glycosylation at T95 (P = 0.0235);.;.;Gain of glycosylation at T95 (P = 0.0235);
MVP		0.30
MPC		0.40
ClinPred		0.32	T
GERP RS		2.6
Varity_R		0.079
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-164507054;