chr5-16179185-C-A

Variant names:

• chr5-16179185-C-A
• rs766367988
• NM_001102562.3:c.391G>T

Variant summary

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

The NM_001102562.3(MARCHF11):​c.391G>T​(p.Glu131*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,197,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: MARCHF11 NM_001102562.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

Genes affected

MARCHF11 (HGNC:33609): (membrane associated ring-CH-type finger 11) MARCH11 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). These enzymes add ubiquitin (see MIM 191339) to target lysines in substrate proteins, thereby signaling their intracellular transport. March11 appears to have a role in ubiquitin-mediated protein sorting in the trans-Golgi network (TGN)-multivesicular body (MVB) transport pathway (Morokuma et al., 2007 [PubMed 17604280]).[supplied by OMIM, Apr 2010]

MARCHF11-DT (HGNC:55550): (MARCHF11 divergent transcript)

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_001102562.3. 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
	MARCHF11	NM_001102562.3	MANE Select	c.391G>T	p.Glu131*	stop_gained	Exon 1 of 4	NP_001096032.1	A6NNE9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCHF11	ENST00000332432.9	TSL:5 MANE Select	c.391G>T	p.Glu131*	stop_gained	Exon 1 of 4	ENSP00000333181.7	A6NNE9-1
	MARCHF11	ENST00000505509.1	TSL:3	n.119-1304G>T		intron	N/A
	MARCHF11-DT	ENST00000757949.1		n.208+3341C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1197278 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 583388

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23658

American (AMR) AF: 0.00 AC: 0 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16526

East Asian (EAS) AF: 0.00 AC: 0 AN: 26790

South Asian (SAS) AF: 0.00 AC: 0 AN: 48486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3334

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 990908

Other (OTH) AF: 0.00 AC: 0 AN: 48846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.0018	N
PhyloP100		1.4
Vest4		0.055
GERP RS		2.3
Mutation Taster		=23/177	disease causing (fs/PTC)

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: rs766367988; hg19: chr5-16179294;