20-37179387-G-GCTTATAGACAGGCCCCCGCGGCCGGCACT

Variant names:

• chr20-37179387-G-GCTTATAGACAGGCCCCCGCGGCCGGCACT
• rs11467214
• NM_152503.8:c.92+1_93insAGTGCCGGCCGCGGGGGCCTGTCTATAAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_152503.8(MROH8):​c.92+1_93insAGTGCCGGCCGCGGGGGCCTGTCTATAAG variant causes a splice acceptor, splice donor, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MROH8 NM_152503.8 splice_acceptor, splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.659
• Publications: 9 publications found

Genes affected

MROH8 (HGNC:16125): (maestro heat like repeat family member 8) The protein encoded by this gene belongs to the maestro heat-like repeat family. The exact function of this gene is not known, however, in a genome-wide association study using hippocampal atrophy as a quantitative trait, this gene has been associated with Alzheimer's disease (PMID:19668339). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

RPN2 (HGNC:10382): (ribophorin II) This gene encodes a type I integral membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0527325 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of -29, new splice context is: cgacagccctctccccaaAGagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152503.8. 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
	MROH8	NM_152503.8	MANE Select	c.92+1_93insAGTGCCGGCCGCGGGGGCCTGTCTATAAG		splice_acceptor splice_donor intron	N/A	NP_689716.4
	RPN2	NM_002951.5	MANE Select	c.13+21_13+22insATAGACAGGCCCCCGCGGCCGGCACTCTT		intron	N/A	NP_002942.2
	RPN2	NM_001324301.2		c.13+21_13+22insATAGACAGGCCCCCGCGGCCGGCACTCTT		intron	N/A	NP_001311230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPN2	ENST00000237530.11	TSL:1 MANE Select	c.13+18_13+19insCTTATAGACAGGCCCCCGCGGCCGGCACT		intron	N/A	ENSP00000237530.6
	MROH8	ENST00000343811.10	TSL:1	c.92+1_93insAGTGCCGGCCGCGGGGGCCTGTCTATAAG		splice_acceptor splice_donor intron	N/A	ENSP00000513568.1
	MROH8	ENST00000400440.7	TSL:1	c.92+1_93insAGTGCCGGCCGCGGGGGCCTGTCTATAAG		splice_acceptor splice_donor intron	N/A	ENSP00000513569.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151894 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000295 AC: 4 AN: 1355844 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 663772

African (AFR) AF: 0.000130 AC: 4 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 34726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24572

East Asian (EAS) AF: 0.00 AC: 0 AN: 34844

South Asian (SAS) AF: 0.00 AC: 0 AN: 77664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4968

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056358

Other (OTH) AF: 0.00 AC: 0 AN: 56182

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151894 Hom.: 0 Cov.: 0 AF XY: 0.0000270 AC XY: 2 AN XY: 74178

African (AFR) AF: 0.000193 AC: 8 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 4465

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=36/64	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11467214; hg19: chr20-35807790;