rs61744585

Variant names:

• chr9-137096361-C-T
• rs61744585
• NM_016219.5:c.590C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016219.5(MAN1B1):​c.590C>T​(p.Pro197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,613,756 control chromosomes in the GnomAD database, including 1,145 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1049 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.360
• Publications: 10 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: ClinGen, Orphanet
• Rafiq syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, 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=0.0012768805).
• BP6: Variant 9-137096361-C-T is Benign according to our data. Variant chr9-137096361-C-T is described in ClinVar as Benign. ClinVar VariationId is 129580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0921 is higher than 0.05.

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.590C>T	p.Pro197Leu	missense	Exon 4 of 13	NP_057303.2	Q9UKM7
	MAN1B1	NR_045720.2		n.605C>T		non_coding_transcript_exon	Exon 4 of 13
	MAN1B1	NR_045721.2		n.736C>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.590C>T	p.Pro197Leu	missense	Exon 4 of 13	ENSP00000360645.4	Q9UKM7
	MAN1B1	ENST00000371587.9	TSL:1	n.*292C>T		non_coding_transcript_exon	Exon 5 of 14	ENSP00000483132.2	A0A087X064
	MAN1B1	ENST00000544448.6	TSL:1	n.590C>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000444966.2	H0YGV7

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2927 AN: 152216 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0374 AC: 9355 AN: 250174 AF XY: 0.0312

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0195 AC: 28482 AN: 1461422 Hom.: 1049 Cov.: 32 AF XY: 0.0187 AC XY: 13628 AN XY: 726976

African (AFR) AF: 0.00400 AC: 134 AN: 33474

American (AMR) AF: 0.180 AC: 8031 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 535 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39690

South Asian (SAS) AF: 0.0183 AC: 1577 AN: 86250

European-Finnish (FIN) AF: 0.00702 AC: 373 AN: 53148

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.0151 AC: 16829 AN: 1111934

Other (OTH) AF: 0.0162 AC: 979 AN: 60366

GnomAD4 genome AF: 0.0193 AC: 2933 AN: 152334 Hom.: 96 Cov.: 32 AF XY: 0.0203 AC XY: 1513 AN XY: 74478

African (AFR) AF: 0.00483 AC: 201 AN: 41580

American (AMR) AF: 0.0961 AC: 1471 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4832

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0147 AC: 1001 AN: 68022

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0157 Hom.: 113

Bravo AF: 0.0278

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0311 AC: 3775

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0132

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.42
DANN	Benign	0.89
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.36
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.060
Sift	Benign	0.098	T
Sift4G	Benign	0.31	T
Polyphen		0.59	P
Vest4		0.069
MPC		0.087
ClinPred		0.0032	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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: rs61744585; hg19: chr9-139990813; COSMIC: COSV63034911;