chr5-10391705-C-G

Variant names:

• chr5-10391705-C-G
• rs757101939
• NM_005885.4:c.740C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005885.4(MARCHF6):​c.740C>G​(p.Ala247Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A247V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MARCHF6 NM_005885.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.943
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05089146).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF6	NM_005885.4	MANE Select	c.740C>G	p.Ala247Gly	missense	Exon 7 of 26	NP_005876.2
	MARCHF6	NM_001270660.2		c.596C>G	p.Ala199Gly	missense	Exon 6 of 25	NP_001257589.1	O60337-5
	MARCHF6	NM_001270661.2		c.425C>G	p.Ala142Gly	missense	Exon 4 of 23	NP_001257590.1	O60337-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF6	ENST00000274140.10	TSL:1 MANE Select	c.740C>G	p.Ala247Gly	missense	Exon 7 of 26	ENSP00000274140.4	O60337-4
	MARCHF6	ENST00000930189.1		c.740C>G	p.Ala247Gly	missense	Exon 7 of 27	ENSP00000600248.1
	MARCHF6	ENST00000863549.1		c.740C>G	p.Ala247Gly	missense	Exon 7 of 26	ENSP00000533608.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426078 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 706834

African (AFR) AF: 0.00 AC: 0 AN: 31774

American (AMR) AF: 0.00 AC: 0 AN: 39192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24182

East Asian (EAS) AF: 0.00 AC: 0 AN: 38076

South Asian (SAS) AF: 0.00 AC: 0 AN: 82224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093648

Other (OTH) AF: 0.00 AC: 0 AN: 58754

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Benign	0.94
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.94
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.025
Sift	Benign	0.37	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.16
MutPred		0.20		Gain of loop (P = 0.0079)
MVP		0.14
MPC		0.69
ClinPred		0.061	T
GERP RS		2.2
Varity_R		0.016
gMVP		0.33
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs757101939; hg19: chr5-10391817;