rs73569515

Variant names:

• chr9-137096373-C-T
• rs73569515
• NM_016219.5:c.602C>T
• MAN1B1 p.Pro201Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016219.5(MAN1B1):​c.602C>T​(p.Pro201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,714 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P201P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.962
• Publications: 5 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025528073).
• BP6: Variant 9-137096373-C-T is Benign according to our data. Variant chr9-137096373-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1537/152332) while in subpopulation AFR AF = 0.0351 (1459/41578). AF 95% confidence interval is 0.0336. There are 40 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	NM_016219.5	MANE Select	c.602C>T	p.Pro201Leu	missense	Exon 4 of 13	NP_057303.2	Q9UKM7
	MAN1B1	NR_045720.2		n.617C>T		non_coding_transcript_exon	Exon 4 of 13
	MAN1B1	NR_045721.2		n.748C>T		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.602C>T	p.Pro201Leu	missense	Exon 4 of 13	ENSP00000360645.4	Q9UKM7
	MAN1B1	ENST00000371587.9	TSL:1	n.*304C>T		non_coding_transcript_exon	Exon 5 of 14	ENSP00000483132.2	A0A087X064
	MAN1B1	ENST00000544448.6	TSL:1	n.602C>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000444966.2	H0YGV7

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1533 AN: 152214 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00277 AC: 692 AN: 249926 AF XY: 0.00193

Gnomad AFR exome AF: 0.0373

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00108 AC: 1584 AN: 1461382 Hom.: 15 Cov.: 32 AF XY: 0.000959 AC XY: 697 AN XY: 726956

African (AFR) AF: 0.0350 AC: 1173 AN: 33474

American (AMR) AF: 0.00224 AC: 100 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53084

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111926

Other (OTH) AF: 0.00252 AC: 152 AN: 60366

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152332 Hom.: 40 Cov.: 32 AF XY: 0.00966 AC XY: 720 AN XY: 74498

African (AFR) AF: 0.0351 AC: 1459 AN: 41578

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00474 Hom.: 12

Bravo AF: 0.0114

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Rafiq syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.19
DANN	Benign	0.72
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.96
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.096
Sift	Benign	0.38	T
Sift4G	Benign	0.37	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.14
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs73569515;

hg19: chr9-139990825;