rs16855795

Variant names:

• chr2-216259654-C-T
• rs16855795
• NM_020814.3:c.891G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020814.3(MARCHF4):​c.891G>A​(p.Ser297Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,994 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (86 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (76 hom.)
• Consequence: MARCHF4 NM_020814.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.46

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-216259654-C-T is Benign according to our data. Variant chr2-216259654-C-T is described in ClinVar as [Benign]. Clinvar id is 769585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF4	NM_020814.3	c.891G>A	p.Ser297Ser	synonymous_variant	Exon 4 of 4	ENST00000273067.5	NP_065865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF4	ENST00000273067.5	c.891G>A	p.Ser297Ser	synonymous_variant	Exon 4 of 4	1	NM_020814.3	ENSP00000273067.3
ENSG00000231092	ENST00000417481.1	n.60C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2760 AN: 152128 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00512 AC: 1282 AN: 250352 Hom.: 40 AF XY: 0.00399 AC XY: 540 AN XY: 135434

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00282 AC: 4116 AN: 1461748 Hom.: 76 Cov.: 33 AF XY: 0.00253 AC XY: 1839 AN XY: 727164

Gnomad4 AFR exome AF: 0.0625

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.0182 AC: 2767 AN: 152246 Hom.: 86 Cov.: 32 AF XY: 0.0179 AC XY: 1333 AN XY: 74442

Gnomad4 AFR AF: 0.0613

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00553 Hom.: 20

Bravo AF: 0.0206

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.058
DANN	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs16855795; hg19: chr2-217124377;