chr2-216259367-T-G

Variant names:

• chr2-216259367-T-G
• rs539418809
• NM_020814.3:c.1178A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020814.3(MARCHF4):​c.1178A>C​(p.Gln393Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q393R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MARCHF4 NM_020814.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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]

ENSG00000231092 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06389788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020814.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF4	NM_020814.3	MANE Select	c.1178A>C	p.Gln393Pro	missense	Exon 4 of 4	NP_065865.1	Q9P2E8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF4	ENST00000273067.5	TSL:1 MANE Select	c.1178A>C	p.Gln393Pro	missense	Exon 4 of 4	ENSP00000273067.3	Q9P2E8
	ENSG00000231092	ENST00000417481.1	TSL:2	n.-228T>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443256 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714786

African (AFR) AF: 0.0000303 AC: 1 AN: 33020

American (AMR) AF: 0.00 AC: 0 AN: 43334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 84674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099638

Other (OTH) AF: 0.00 AC: 0 AN: 59442

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.0054
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.075
Sift	Benign	0.37	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.086
MutPred		0.10		Gain of glycosylation at Q393 (P = 0.0135)
MVP		0.44
MPC		0.64
ClinPred		0.34	T
GERP RS		5.5
Varity_R		0.21
gMVP		0.31
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs539418809; hg19: chr2-217124090;