dbSNP rs3764990: MARCHF8:p.Pro374Ser (chr10-45461380-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.03

Publications

22 publications found

Variant links:

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]

MARCHF8 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF8	NM_001282866.2 link	c.1120C>T	p.Pro374Ser	missense_variant	Exon 6 of 8	ENST00000453424.7	NP_001269795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF8	ENST00000453424.7 link	c.1120C>T	p.Pro374Ser	missense_variant	Exon 6 of 8	1	NM_001282866.2	ENSP00000411848.2		Q5T0T0-2

Frequencies

GnomAD3 genomes

AF:

0.0488

AC:

7422

AN:

152110

Hom.:

252

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0623

AC XY:

44666

AN XY:

716670

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4093

8186

12279

16372

20465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0488

AC:

7422

AN:

152228

Hom.:

255

Cov.:

AF XY:

0.0491

AC XY:

3657

AN XY:

74412

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0664

AC:

4517

AN:

68028

Other (OTH)

AF:

0.0459

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

366

731

1097

1462

1828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

.;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;.

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;M;M

PhyloP100

8.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.7

.;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.069

.;T;T

Sift4G

Uncertain

0.036

D;D;D

Polyphen

0.83

.;P;P

Vest4

0.29

ClinPred

0.024

GERP RS

5.7

Varity_R

0.54

gMVP

0.68

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

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rs3764990

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over