rs118117962

Variant names:

• chr9-137108543-C-T
• rs118117962
• NM_016219.5:c.2052C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_016219.5(MAN1B1):​c.2052C>T​(p.Tyr684Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,613,800 control chromosomes in the GnomAD database, including 1,258 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (95 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1163 hom.)
• Consequence: MAN1B1 NM_016219.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.75
• 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: ClinGen, Orphanet
• Rafiq syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 9-137108543-C-T is Benign according to our data. Variant chr9-137108543-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0289 (4397/152298) while in subpopulation NFE AF = 0.0418 (2845/68020). AF 95% confidence interval is 0.0405. There are 95 homozygotes in GnomAd4. There are 2092 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 95 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.2052C>T	p.Tyr684Tyr	synonymous	Exon 13 of 13	NP_057303.2	Q9UKM7
	MAN1B1	NR_045720.2		n.2042C>T		non_coding_transcript_exon	Exon 13 of 13
	MAN1B1	NR_045721.2		n.2198C>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.2052C>T	p.Tyr684Tyr	synonymous	Exon 13 of 13	ENSP00000360645.4	Q9UKM7
	MAN1B1	ENST00000371587.9	TSL:1	n.*1729C>T		non_coding_transcript_exon	Exon 14 of 14	ENSP00000483132.2	A0A087X064
	MAN1B1	ENST00000544448.6	TSL:1	n.*335C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000444966.2	H0YGV7

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4397 AN: 152180 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0714

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0302 AC: 7598 AN: 251480 AF XY: 0.0311

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0687

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0373 AC: 54570 AN: 1461502 Hom.: 1163 Cov.: 35 AF XY: 0.0370 AC XY: 26920 AN XY: 727054

African (AFR) AF: 0.00535 AC: 179 AN: 33478

American (AMR) AF: 0.0186 AC: 833 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 1796 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0214 AC: 1849 AN: 86258

European-Finnish (FIN) AF: 0.0279 AC: 1481 AN: 53168

Middle Eastern (MID) AF: 0.0418 AC: 241 AN: 5768

European-Non Finnish (NFE) AF: 0.0415 AC: 46122 AN: 1111888

Other (OTH) AF: 0.0342 AC: 2063 AN: 60388

GnomAD4 genome AF: 0.0289 AC: 4397 AN: 152298 Hom.: 95 Cov.: 32 AF XY: 0.0281 AC XY: 2092 AN XY: 74462

African (AFR) AF: 0.00717 AC: 298 AN: 41572

American (AMR) AF: 0.0299 AC: 457 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 248 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4822

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2845 AN: 68020

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0381 Hom.: 56

Bravo AF: 0.0285

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.65
DANN	Benign	0.82
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs118117962; hg19: chr9-140002995; COSMIC: COSV65370916; COSMIC: COSV65370916;