9-137086979-C-A

Variant names:

• chr9-137086979-C-A
• rs367593587
• ENST00000371587.9:n.-21C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000371587.9(MAN1B1):​n.-21C>A variant causes a non coding transcript exon 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 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.661
• Publications: 0 publications found

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]

MAN1B1-DT (HGNC:48715): (MAN1B1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 182 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.-21C>A		upstream_gene_variant		ENST00000371589.9	NP_057303.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.-21C>A		upstream_gene_variant		1	NM_016219.5	ENSP00000360645.4

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

GnomAD2 exomes AF: 0.000268 AC: 49 AN: 182732 AF XY: 0.000285

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 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

African (AFR) AF: 0.000516 AC: 17 AN: 32938

American (AMR) AF: 0.000661 AC: 25 AN: 37840

Ashkenazi Jewish (ASJ) AF: 0.0000792 AC: 2 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 38152

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81008

European-Finnish (FIN) AF: 0.0000412 AC: 2 AN: 48506

Middle Eastern (MID) AF: 0.00430 AC: 23 AN: 5346

European-Non Finnish (NFE) AF: 0.000212 AC: 232 AN: 1091800

Other (OTH) AF: 0.000730 AC: 43 AN: 58898

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

African (AFR) AF: 0.000481 AC: 20 AN: 41594

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68046

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000366

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual Disability, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.66
PromoterAI		-0.0098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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: rs367593587; hg19: chr9-139981431;