chr10-45461380-G-C

Variant names:

• chr10-45461380-G-C
• rs3764990
• NM_001282866.2:c.1120C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001282866.2(MARCHF8):​c.1120C>G​(p.Pro374Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,440,910 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MARCHF8 NM_001282866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03
• Publications: 22 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282866.2. 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
	MARCHF8	NM_001282866.2	MANE Select	c.1120C>G	p.Pro374Ala	missense	Exon 6 of 8	NP_001269795.1	Q5T0T0-2
	MARCHF8	NM_001401645.1		c.1120C>G	p.Pro374Ala	missense	Exon 7 of 9	NP_001388574.1	Q5T0T0-2
	MARCHF8	NM_001401646.1		c.1120C>G	p.Pro374Ala	missense	Exon 6 of 8	NP_001388575.1	Q5T0T0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF8	ENST00000453424.7	TSL:1 MANE Select	c.1120C>G	p.Pro374Ala	missense	Exon 6 of 8	ENSP00000411848.2	Q5T0T0-2
	MARCHF8	ENST00000319836.7	TSL:1	c.274C>G	p.Pro92Ala	missense	Exon 5 of 7	ENSP00000317087.3	Q5T0T0-1
	MARCHF8	ENST00000395769.6	TSL:1	c.274C>G	p.Pro92Ala	missense	Exon 5 of 7	ENSP00000379116.2	Q5T0T0-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 231222 AF XY: 0.0000239

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000486 AC: 7 AN: 1440910 Hom.: 0 Cov.: 31 AF XY: 0.00000977 AC XY: 7 AN XY: 716778

African (AFR) AF: 0.00 AC: 0 AN: 32136

American (AMR) AF: 0.00 AC: 0 AN: 40674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 38060

South Asian (SAS) AF: 0.0000837 AC: 7 AN: 83608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103022

Other (OTH) AF: 0.00 AC: 0 AN: 59386

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Uncertain	0.048	D
Polyphen		0.33	B
Vest4		0.55
MutPred		0.48		Loss of disorder (P = 0.063)
MVP		0.82
ClinPred		0.48	T
GERP RS		5.7
Varity_R		0.47
gMVP		0.60
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs3764990; hg19: chr10-45956828;