2-216315809-C-T

Position:

• chr2-216315809-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020814.3(MARCHF4):​c.517-32080G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,950 control chromosomes in the GnomAD database, including 12,992 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 0.40 (12992 hom., cov: 32)
• Consequence: MARCHF4 NM_020814.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.313

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARCHF4	NM_020814.3	c.517-32080G>A		intron_variant		ENST00000273067.5
LOC107985983	XR_001739877.2	n.353-2269C>T		intron_variant, non_coding_transcript_variant
LOC107985983	XR_001739876.2	n.353-2269C>T		intron_variant, non_coding_transcript_variant
LOC107985983	XR_001739878.2	n.348-2269C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARCHF4	ENST00000273067.5	c.517-32080G>A		intron_variant		1	NM_020814.3	P1
	ENST00000452736.1	n.336-2269C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60661 AN: 151832 Hom.: 12987 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.399 AC: 60691 AN: 151950 Hom.: 12992 Cov.: 32 AF XY: 0.405 AC XY: 30098 AN XY: 74248

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.477

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.415

Alfa AF: 0.415 Hom.: 2906

Bravo AF: 0.379

Asia WGS AF: 0.416 AC: 1450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.6
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1851328; hg19: chr2-217180532; COSMIC: COSV56103843;