9-137106299-G-T

Variant names:

• chr9-137106299-G-T
• rs75639549
• NM_016219.5:c.1429G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016219.5(MAN1B1):​c.1429G>T​(p.Gly477Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G477R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• 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 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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.1429G>T	p.Gly477Trp	missense	Exon 9 of 13	NP_057303.2
	MAN1B1	NR_045720.2		n.1444G>T		non_coding_transcript_exon	Exon 9 of 13
	MAN1B1	NR_045721.2		n.1575G>T		non_coding_transcript_exon	Exon 10 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.1429G>T	p.Gly477Trp	missense	Exon 9 of 13	ENSP00000360645.4
	MAN1B1	ENST00000371587.9	TSL:1	n.*1131G>T		non_coding_transcript_exon	Exon 10 of 14	ENSP00000483132.2
	MAN1B1	ENST00000544448.6	TSL:1	n.1429G>T		non_coding_transcript_exon	Exon 9 of 13	ENSP00000444966.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691422

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 35906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25186

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36440

South Asian (SAS) AF: 0.00 AC: 0 AN: 79660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081214

Other (OTH) AF: 0.00 AC: 0 AN: 58018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.60		Loss of disorder (P = 0.0106)
MVP		0.95
MPC		0.47
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.76
Mutation Taster		=48/52	disease causing

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: rs75639549; hg19: chr9-140000751;