19-8426644-C-T

Variant names:

• chr19-8426644-C-T
• rs763102811
• NM_001005415.2:c.212C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005415.2(MARCHF2):​c.212C>T​(p.Ala71Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000643 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A71G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: MARCHF2 NM_001005415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76
• Publications: 1 publications found

Genes affected

MARCHF2 (HGNC:28038): (membrane associated ring-CH-type finger 2) MARCH2 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. MARCH2 reduces surface accumulation of several glycoproteins and appears to regulate early endosome-to-trans-Golgi network (TGN) trafficking (Bartee et al., 2004 [PubMed 14722266]; Nakamura et al., 2005 [PubMed 15689499]).[supplied by OMIM, Mar 2010]

ENSG00000268931 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25344062).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005415.2. 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
	MARCHF2	NM_001005415.2	MANE Select	c.212C>T	p.Ala71Val	missense	Exon 3 of 5	NP_001005415.1	Q9P0N8-1
	MARCHF2	NM_001369776.1		c.212C>T	p.Ala71Val	missense	Exon 4 of 6	NP_001356705.1	Q9P0N8-1
	MARCHF2	NM_001369777.1		c.212C>T	p.Ala71Val	missense	Exon 4 of 6	NP_001356706.1	Q9P0N8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF2	ENST00000215555.7	TSL:5 MANE Select	c.212C>T	p.Ala71Val	missense	Exon 3 of 5	ENSP00000215555.2	Q9P0N8-1
	MARCHF2	ENST00000602117.1	TSL:1	c.212C>T	p.Ala71Val	missense	Exon 3 of 5	ENSP00000471536.1	Q9P0N8-1
	MARCHF2	ENST00000860161.1		c.332C>T	p.Ala111Val	missense	Exon 5 of 7	ENSP00000530220.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251262 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111986

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0096	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.53	N
PhyloP100		5.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.38	T
Sift4G	Benign	0.34	T
Polyphen		0.95	P
Vest4		0.40
MVP		0.77
MPC		0.59
ClinPred		0.38	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.39
Mutation Taster		=94/6	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: rs763102811; hg19: chr19-8491528; COSMIC: COSV99294889; COSMIC: COSV99294889;