10-45461380-G-A

Variant names:

• chr10-45461380-G-A
• rs3764990
• NM_001282866.2:c.1120C>T

Variant summary

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

The NM_001282866.2(MARCHF8):​c.1120C>T​(p.Pro374Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.062 in 1,592,906 control chromosomes in the GnomAD database, including 3,422 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 0.049 (255 hom., cov: 33)
  • Exomes 𝑓: 0.063 (3167 hom.)
• Consequence: MARCHF8 NM_001282866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03
• Publications: 22 publications found

Genes affected

MARCHF8 (HGNC:23356): (membrane associated ring-CH-type finger 8) MARCH8 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. MARCH8 induces the internalization of several membrane glycoproteins (Goto et al., 2003 [PubMed 12582153]; Bartee et al., 2004 [PubMed 14722266]).[supplied by OMIM, Apr 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0141607225).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282866.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF8	NM_001282866.2	MANE Select	c.1120C>T	p.Pro374Ser	missense	Exon 6 of 8	NP_001269795.1
	MARCHF8	NM_001401645.1		c.1120C>T	p.Pro374Ser	missense	Exon 7 of 9	NP_001388574.1
	MARCHF8	NM_001401646.1		c.1120C>T	p.Pro374Ser	missense	Exon 6 of 8	NP_001388575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF8	ENST00000453424.7	TSL:1 MANE Select	c.1120C>T	p.Pro374Ser	missense	Exon 6 of 8	ENSP00000411848.2
	MARCHF8	ENST00000319836.7	TSL:1	c.274C>T	p.Pro92Ser	missense	Exon 5 of 7	ENSP00000317087.3
	MARCHF8	ENST00000395769.6	TSL:1	c.274C>T	p.Pro92Ser	missense	Exon 5 of 7	ENSP00000379116.2

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7422 AN: 152110 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.0400

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0503 AC: 11627 AN: 231222 AF XY: 0.0499

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0359

Gnomad EAS exome AF: 0.0416

Gnomad FIN exome AF: 0.0785

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0634 AC: 91379 AN: 1440678 Hom.: 3167 Cov.: 31 AF XY: 0.0623 AC XY: 44666 AN XY: 716670

African (AFR) AF: 0.0197 AC: 634 AN: 32134

American (AMR) AF: 0.0301 AC: 1225 AN: 40654

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 958 AN: 25372

East Asian (EAS) AF: 0.0862 AC: 3280 AN: 38054

South Asian (SAS) AF: 0.0227 AC: 1900 AN: 83602

European-Finnish (FIN) AF: 0.0771 AC: 4093 AN: 53090

Middle Eastern (MID) AF: 0.0339 AC: 188 AN: 5542

European-Non Finnish (NFE) AF: 0.0687 AC: 75804 AN: 1102854

Other (OTH) AF: 0.0555 AC: 3297 AN: 59376

GnomAD4 genome AF: 0.0488 AC: 7422 AN: 152228 Hom.: 255 Cov.: 33 AF XY: 0.0491 AC XY: 3657 AN XY: 74412

African (AFR) AF: 0.0195 AC: 808 AN: 41530

American (AMR) AF: 0.0450 AC: 688 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 139 AN: 3472

East Asian (EAS) AF: 0.0516 AC: 267 AN: 5176

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4824

European-Finnish (FIN) AF: 0.0692 AC: 733 AN: 10588

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4517 AN: 68028

Other (OTH) AF: 0.0459 AC: 97 AN: 2114

Alfa AF: 0.0548 Hom.: 214

Bravo AF: 0.0456

TwinsUK AF: 0.0693 AC: 257

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.0603 AC: 519

ExAC AF: 0.0501 AC: 6078

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.31
Sift	Benign	0.069	T
Sift4G	Uncertain	0.036	D
Polyphen		0.83	P
Vest4		0.29
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.68
Mutation Taster		=82/18	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: rs3764990; hg19: chr10-45956828; COSMIC: COSV60572189; COSMIC: COSV60572189;