Variant 5-10391640-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005885.4(MARCHF6):c.675G>C(p.Gln225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.8e-7 ( 0 hom. )

Consequence

MARCHF6
NM_005885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MARCHF6. . Gene score misZ 3.8752 (greater than the threshold 3.09). Trascript score misZ 3.9738 (greater than threshold 3.09). GenCC has associacion of gene with benign adult familial myoclonic epilepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.105638474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCHF6	NM_005885.4 linkuse as main transcript	c.675G>C	p.Gln225His	missense_variant	7/26	ENST00000274140.10	NP_005876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCHF6	ENST00000274140.10 linkuse as main transcript	c.675G>C	p.Gln225His	missense_variant	7/26	1	NM_005885.4	ENSP00000274140	P1	O60337-4
MARCHF6	ENST00000449913.6 linkuse as main transcript	c.531G>C	p.Gln177His	missense_variant	6/25	2		ENSP00000414643		O60337-5
MARCHF6	ENST00000503788.5 linkuse as main transcript	c.360G>C	p.Gln120His	missense_variant	4/23	2		ENSP00000425930		O60337-6
MARCHF6	ENST00000511802.5 linkuse as main transcript	n.859G>C		non_coding_transcript_exon_variant	7/25	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246812

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133780

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459908

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.675G>C (p.Q225H) alteration is located in exon 7 (coding exon 7) of the MARCH6 gene. This alteration results from a G to C substitution at nucleotide position 675, causing the glutamine (Q) at amino acid position 225 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

.;.;T

Eigen

Benign

-0.016

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0074

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.055

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.098

T;T;T

Polyphen

0.84

.;.;P

Vest4

0.23

MutPred

0.11

.;.;Gain of loop (P = 0.0312);

MVP

0.22

MPC

0.80

ClinPred

0.21

GERP RS

4.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.7

Varity_R

0.073

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over