9-137106750-G-T

Variant names:

• chr9-137106750-G-T
• rs757690679
• NM_016219.5:c.1507G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_016219.5(MAN1B1):​c.1507G>T​(p.Glu503*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN1B1 NM_016219.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.453
• Publications: 1 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 Gene-Disease associations (from GenCC):

• MAN1B1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Rafiq syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	NM_016219.5	MANE Select	c.1507G>T	p.Glu503*	stop_gained	Exon 10 of 13	NP_057303.2
	MAN1B1	NR_045720.2		n.1522G>T		non_coding_transcript_exon	Exon 10 of 13
	MAN1B1	NR_045721.2		n.1653G>T		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.1507G>T	p.Glu503*	stop_gained	Exon 10 of 13	ENSP00000360645.4
	MAN1B1	ENST00000371587.9	TSL:1	n.*1209G>T		non_coding_transcript_exon	Exon 11 of 14	ENSP00000483132.2
	MAN1B1	ENST00000544448.6	TSL:1	n.1507G>T		non_coding_transcript_exon	Exon 10 of 13	ENSP00000444966.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250908 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461110 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	-0.0081
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.45
Vest4		0.21
ClinPred		0.94	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs757690679; hg19: chr9-140001202;