Genetic Variant MARCHF6:p.Glu201Ala (chr5-10391567-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005885.4(MARCHF6):c.602A>C(p.Glu201Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,156 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 (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MARCHF6
NM_005885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.96

Publications

0 publications found

Variant links:

Genes affected

MARCHF6 (HGNC:30550): (membrane associated ring-CH-type finger 6) This gene encodes a member of a family of membrane-associated E3 ubiquitin ligases containing RING-CH-type zinc finger motifs. Ubiquitination of type II deiodinase by the encoded protein is an important regulatory step in thyroid hormone signalling. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

MARCHF6 Gene-Disease associations (from GenCC):

benign adult familial myoclonic epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MARCHF6 links:

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ACMG classification

Classification was made for transcript

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=0.1361756).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005885.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARCHF6	NM_005885.4	MANE Select	c.602A>C	p.Glu201Ala	missense	Exon 7 of 26	NP_005876.2
MARCHF6	NM_001270660.2		c.458A>C	p.Glu153Ala	missense	Exon 6 of 25	NP_001257589.1	O60337-5
MARCHF6	NM_001270661.2		c.287A>C	p.Glu96Ala	missense	Exon 4 of 23	NP_001257590.1	O60337-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARCHF6	ENST00000274140.10	TSL:1 MANE Select	c.602A>C	p.Glu201Ala	missense	Exon 7 of 26	ENSP00000274140.4	O60337-4
MARCHF6	ENST00000930189.1		c.602A>C	p.Glu201Ala	missense	Exon 7 of 27	ENSP00000600248.1
MARCHF6	ENST00000863549.1		c.602A>C	p.Glu201Ala	missense	Exon 7 of 26	ENSP00000533608.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460156

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33296

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111112

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

Eigen

Benign

-0.062

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Benign

0.0031

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.86

PhyloP100

8.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.84

REVEL

Benign

0.067

Sift

Benign

0.33

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.55

MutPred

0.19

Gain of helix (P = 0.062)

MVP

0.19

MPC

0.73

ClinPred

0.70

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.28

Mutation Taster

=41/59

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over