2-216322018-T-C

Variant names:

• chr2-216322018-T-C
• rs6728666
• NM_020814.3:c.517-38289A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020814.3(MARCHF4):​c.517-38289A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 152,030 control chromosomes in the GnomAD database, including 28,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (28542 hom., cov: 32)
• Consequence: MARCHF4 NM_020814.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 4 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]

MARCHF4-AS1 (HGNC:58229):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

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.517-38289A>G		intron	N/A	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.517-38289A>G		intron	N/A	ENSP00000273067.3	Q9P2E8

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91362 AN: 151912 Hom.: 28474 Cov.: 32

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.586

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.602 AC: 91495 AN: 152030 Hom.: 28542 Cov.: 32 AF XY: 0.601 AC XY: 44600 AN XY: 74266

African (AFR) AF: 0.747 AC: 30975 AN: 41490

American (AMR) AF: 0.651 AC: 9941 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1705 AN: 3472

East Asian (EAS) AF: 0.788 AC: 4061 AN: 5154

South Asian (SAS) AF: 0.639 AC: 3079 AN: 4822

European-Finnish (FIN) AF: 0.467 AC: 4920 AN: 10534

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34931 AN: 67984

Other (OTH) AF: 0.590 AC: 1247 AN: 2112

Alfa AF: 0.536 Hom.: 43763

Bravo AF: 0.622

Asia WGS AF: 0.738 AC: 2568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.32
DANN	Benign	0.47
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs6728666; hg19: chr2-217186741;