17-62725057-C-T

Position:

• chr17-62725057-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP3 BP4_Strong BP6 BS1 BS2

The NM_152598.4(MARCHF10):​c.1985G>A​(p.Cys662Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,606,550 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (8 hom.)
• Consequence: MARCHF10 NM_152598.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.91

Genes affected

MARCHF10 (HGNC:26655): (membrane associated ring-CH-type finger 10) MARCH10 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 (Morokuma et al., 2007 [PubMed 17604280]).[supplied by OMIM, Apr 2010]

ENSG00000265702 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MARHA_HUMAN
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.016122937).
• BP6: Variant 17-62725057-C-T is Benign according to our data. Variant chr17-62725057-C-T is described in ClinVar as [Benign]. Clinvar id is 3053092.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00582 (887/152350) while in subpopulation AFR AF= 0.02 (833/41584). AF 95% confidence interval is 0.0189. There are 4 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCHF10	NM_152598.4	c.1985G>A	p.Cys662Tyr	missense_variant	7/11	ENST00000311269.10	NP_689811.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCHF10	ENST00000311269.10	c.1985G>A	p.Cys662Tyr	missense_variant	7/11	2	NM_152598.4	ENSP00000311496.5

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 887 AN: 152232 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00163 AC: 396 AN: 242516 Hom.: 3 AF XY: 0.00113 AC XY: 149 AN XY: 131442

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00131

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: 0.0000897

Gnomad OTH exome AF: 0.000864

GnomAD4 exome AF: 0.000637 AC: 926 AN: 1454200 Hom.: 8 Cov.: 31 AF XY: 0.000570 AC XY: 412 AN XY: 723428

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000919

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00582 AC: 887 AN: 152350 Hom.: 4 Cov.: 32 AF XY: 0.00572 AC XY: 426 AN XY: 74506

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00122 Hom.: 2

Bravo AF: 0.00660

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00209 AC: 254

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MARCHF10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Benign	0.93
DEOGEN2	Benign	0.31	.;T;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.5	.;H;H;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-11	.;D;D;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;D
Vest4		0.86, 0.86, 0.90, 0.89
MVP		0.77
MPC		0.79
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.94
gMVP		0.97

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

Other links and lift over

dbSNP: rs80285368; hg19: chr17-60802418;