9-137086979-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000371587.9(MAN1B1):c.-21C>A variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,572,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: MAN1B1 ENST00000371587.9 5_prime_UTR, NMD_transcript
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.661

Genes affected

MAN1B1 (HGNC:6823): (mannosidase alpha class 1B member 1) This gene encodes an enzyme belonging to the glycosyl hydrolase 47 family. This enzyme functions in N-glycan biosynthesis, and is a class I alpha-1,2-mannosidase that specifically converts Man9GlcNAc to Man8GlcNAc isomer B. It is required for N-glycan trimming to Man5-6GlcNAc2 in the endoplasmic-reticulum-associated degradation pathway. Mutations in this gene cause autosomal-recessive intellectual disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 11. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000244 (347/1419744) while in subpopulation MID AF= 0.0043 (23/5346). AF 95% confidence interval is 0.00294. There are 1 homozygotes in gnomad4_exome. There are 182 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1B1	NM_016219.5			upstream_gene_variant		ENST00000371589.9
MAN1B1	XM_006716945.5			upstream_gene_variant
MAN1B1	NR_045720.2			upstream_gene_variant
MAN1B1	NR_045721.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9			upstream_gene_variant		1	NM_016219.5	P2

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152276 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000268 AC: 49 AN: 182732 Hom.: 0 AF XY: 0.000285 AC XY: 28 AN XY: 98182

Gnomad AFR exome AF: 0.000536

Gnomad AMR exome AF: 0.000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.000417

GnomAD4 exome AF: 0.000244 AC: 347 AN: 1419744 Hom.: 1 Cov.: 30 AF XY: 0.000259 AC XY: 182 AN XY: 702630

Gnomad4 AFR exome AF: 0.000516

Gnomad4 AMR exome AF: 0.000661

Gnomad4 ASJ exome AF: 0.0000792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000412

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.000730

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152394 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74532

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000366

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	14
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs367593587; hg19: chr9-139981431;