rs7908745

Variant names:

• chr10-45458319-A-G
• rs7908745
• NM_001282866.2:c.1642T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282866.2(MARCHF8):​c.1642T>C​(p.Tyr548His) variant causes a missense change. The variant allele was found at a frequency of 0.314 in 1,613,644 control chromosomes in the GnomAD database, including 81,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8238 hom., cov: 33)
  • Exomes 𝑓: 0.31 (72962 hom.)
• Consequence: MARCHF8 NM_001282866.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32
• Publications: 47 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030372143).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF8	NM_001282866.2	c.1642T>C	p.Tyr548His	missense_variant	Exon 8 of 8	ENST00000453424.7	NP_001269795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF8	ENST00000453424.7	c.1642T>C	p.Tyr548His	missense_variant	Exon 8 of 8	1	NM_001282866.2	ENSP00000411848.2
MARCHF8	ENST00000319836.7	c.796T>C	p.Tyr266His	missense_variant	Exon 7 of 7	1		ENSP00000317087.3
MARCHF8	ENST00000395769.6	c.796T>C	p.Tyr266His	missense_variant	Exon 7 of 7	1		ENSP00000379116.2
MARCHF8	ENST00000476962.1	n.1347T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49527 AN: 151956 Hom.: 8230 Cov.: 33

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.315 AC: 79102 AN: 251366 AF XY: 0.311

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.313 AC: 457886 AN: 1461570 Hom.: 72962 Cov.: 36 AF XY: 0.311 AC XY: 226439 AN XY: 727086

African (AFR) AF: 0.346 AC: 11580 AN: 33474

American (AMR) AF: 0.394 AC: 17619 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5285 AN: 26134

East Asian (EAS) AF: 0.182 AC: 7209 AN: 39700

South Asian (SAS) AF: 0.296 AC: 25561 AN: 86250

European-Finnish (FIN) AF: 0.362 AC: 19310 AN: 53320

Middle Eastern (MID) AF: 0.252 AC: 1451 AN: 5768

European-Non Finnish (NFE) AF: 0.316 AC: 351608 AN: 1111820

Other (OTH) AF: 0.302 AC: 18263 AN: 60384

GnomAD4 genome AF: 0.326 AC: 49556 AN: 152074 Hom.: 8238 Cov.: 33 AF XY: 0.329 AC XY: 24475 AN XY: 74336

African (AFR) AF: 0.347 AC: 14385 AN: 41474

American (AMR) AF: 0.377 AC: 5768 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3470

East Asian (EAS) AF: 0.166 AC: 857 AN: 5164

South Asian (SAS) AF: 0.289 AC: 1397 AN: 4830

European-Finnish (FIN) AF: 0.356 AC: 3761 AN: 10560

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21589 AN: 67966

Other (OTH) AF: 0.325 AC: 688 AN: 2114

Alfa AF: 0.314 Hom.: 37172

Bravo AF: 0.327

TwinsUK AF: 0.308 AC: 1142

ALSPAC AF: 0.314 AC: 1212

ESP6500AA AF: 0.353 AC: 1554

ESP6500EA AF: 0.304 AC: 2615

ExAC AF: 0.315 AC: 38187

Asia WGS AF: 0.279 AC: 973 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.312

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.0024	.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.066	T;T;.
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	.;N;N
PhyloP100		4.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.55	.;N;N
REVEL	Benign	0.064
Sift	Benign	0.59	.;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.031
ClinPred		0.0052	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs7908745; hg19: chr10-45953767; COSMIC: COSV60572480; COSMIC: COSV60572480;