dbSNP rs80285368: MARCHF10:p.Cys662Tyr (chr17-62725057-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_152598.4(MARCHF10):c.1985G>A(p.Cys662Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,606,550 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 8 hom. )

Consequence

MARCHF10
NM_152598.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.91

Publications

2 publications found

Variant links:

Genes affected

MARCHF10 (HGNC:26655): (membrane associated ring-CH-type finger 10) MARCH10 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 (Morokuma et al., 2007 [PubMed 17604280]).[supplied by OMIM, Apr 2010]

MARCHF10 links:

MARCHF10-AS1 (HGNC:58173):

MARCHF10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.016122937).

BP6

Variant 17-62725057-C-T is Benign according to our data. Variant chr17-62725057-C-T is described in ClinVar as Benign. ClinVar VariationId is 3053092.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00582 (887/152350) while in subpopulation AFR AF = 0.02 (833/41584). AF 95% confidence interval is 0.0189. There are 4 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152598.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARCHF10	NM_152598.4	MANE Select	c.1985G>A	p.Cys662Tyr	missense	Exon 7 of 11	NP_689811.2	A0A140VKA1
MARCHF10	NM_001288779.2		c.2099G>A	p.Cys700Tyr	missense	Exon 8 of 12	NP_001275708.1	J3KTN9
MARCHF10	NM_001100875.3		c.1985G>A	p.Cys662Tyr	missense	Exon 7 of 11	NP_001094345.1	Q8NA82

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARCHF10	ENST00000311269.10	TSL:2 MANE Select	c.1985G>A	p.Cys662Tyr	missense	Exon 7 of 11	ENSP00000311496.5	Q8NA82
MARCHF10	ENST00000583600.5	TSL:1	c.2099G>A	p.Cys700Tyr	missense	Exon 8 of 12	ENSP00000463080.1	J3KTN9
MARCHF10	ENST00000456609.6	TSL:1	c.1985G>A	p.Cys662Tyr	missense	Exon 7 of 11	ENSP00000416177.2	Q8NA82

Frequencies

GnomAD3 genomes

AF:

0.00583

AC:

887

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00163

AC:

396

AN:

242516

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0213

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000897

Gnomad OTH exome

AF:

0.000864

GnomAD4 exome

AF:

0.000637

AC:

926

AN:

1454200

Hom.:

Cov.:

AF XY:

0.000570

AC XY:

412

AN XY:

723428

show subpopulations

African (AFR)

AF:

0.0203

AC:

671

AN:

33096

American (AMR)

AF:

0.00148

AC:

AN:

42692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39244

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000919

AC:

102

AN:

1109338

Other (OTH)

AF:

0.00140

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00582

AC:

887

AN:

152350

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

426

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0200

AC:

833

AN:

41584

American (AMR)

AF:

0.00209

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00660

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00209

AC:

254

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MARCHF10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.31

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

4.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.77

MPC

0.79

ClinPred

0.19

GERP RS

5.4

Varity_R

0.94

gMVP

0.97

Mutation Taster

=91/9

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over