chr20-37179387-G-GCTTATAGACGGGGCCCCGCGGCCGGCACT

Variant names:

• chr20-37179387-G-GCTTATAGACGGGGCCCCGCGGCCGGCACT
• rs11467214
• NM_152503.8:c.92+1_93insAGTGCCGGCCGCGGGGCCCCGTCTATAAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PVS1_Moderate BP6_Moderate

The NM_152503.8(MROH8):​c.92+1_93insAGTGCCGGCCGCGGGGCCCCGTCTATAAG 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0020 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: MROH8 NM_152503.8 splice_acceptor, splice_donor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 0 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.
• BP6: Variant 20-37179387-G-GCTTATAGACGGGGCCCCGCGGCCGGCACT is Benign according to our data. Variant chr20-37179387-G-GCTTATAGACGGGGCCCCGCGGCCGGCACT is described in ClinVar as Likely_benign. ClinVar VariationId is 2041031.Status of the report is criteria_provided_single_submitter, 1 stars.

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_93insAGTGCCGGCCGCGGGGCCCCGTCTATAAG		splice_acceptor splice_donor intron	N/A	NP_689716.4
	RPN2	NM_002951.5	MANE Select	c.13+21_13+22insATAGACGGGGCCCCGCGGCCGGCACTCTT		intron	N/A	NP_002942.2
	RPN2	NM_001324301.2		c.13+21_13+22insATAGACGGGGCCCCGCGGCCGGCACTCTT		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+19insCTTATAGACGGGGCCCCGCGGCCGGCACT		intron	N/A	ENSP00000237530.6	P04844-1
	MROH8	ENST00000343811.10	TSL:1	c.92+1_93insAGTGCCGGCCGCGGGGCCCCGTCTATAAG		splice_acceptor splice_donor intron	N/A	ENSP00000513568.1	A0A8V8TLY2
	MROH8	ENST00000400440.7	TSL:1	c.92+1_93insAGTGCCGGCCGCGGGGCCCCGTCTATAAG		splice_acceptor splice_donor intron	N/A	ENSP00000513569.1	A0A8V8TN72

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 151892 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00287

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00201 AC: 2730 AN: 1355842 Hom.: 3 Cov.: 83 AF XY: 0.00201 AC XY: 1335 AN XY: 663770

African (AFR) AF: 0.000389 AC: 12 AN: 30886

American (AMR) AF: 0.00233 AC: 81 AN: 34726

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 51 AN: 24572

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

South Asian (SAS) AF: 0.00375 AC: 291 AN: 77664

European-Finnish (FIN) AF: 0.000112 AC: 4 AN: 35644

Middle Eastern (MID) AF: 0.000604 AC: 3 AN: 4968

European-Non Finnish (NFE) AF: 0.00206 AC: 2180 AN: 1056356

Other (OTH) AF: 0.00192 AC: 108 AN: 56182

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152008 Hom.: 0 Cov.: 0 AF XY: 0.00108 AC XY: 80 AN XY: 74302

African (AFR) AF: 0.000193 AC: 8 AN: 41466

American (AMR) AF: 0.00196 AC: 30 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00437 AC: 21 AN: 4806

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 67952

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00134 Hom.: 4465

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital disorder of glycosylation (1)

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;