9-137108975-A-G

Variant names:

• chr9-137108975-A-G
• rs4567
• ENST00000371587.9:n.*2161A>G

Variant summary

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

The ENST00000371587.9(MAN1B1):​n.*2161A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 464,886 control chromosomes in the GnomAD database, including 57,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19266 hom., cov: 30)
  • Exomes 𝑓: 0.49 (38252 hom.)
• Consequence: MAN1B1 ENST00000371587.9 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.72
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant 9-137108975-A-G is Benign according to our data. Variant chr9-137108975-A-G is described in ClinVar as Benign. ClinVar VariationId is 365984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371587.9. 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.*384A>G		3_prime_UTR	Exon 13 of 13	NP_057303.2
	MAN1B1	NR_045720.2		n.2474A>G		non_coding_transcript_exon	Exon 13 of 13
	MAN1B1	NR_045721.2		n.2630A>G		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371587.9	TSL:1	n.*2161A>G		non_coding_transcript_exon	Exon 14 of 14	ENSP00000483132.2
	MAN1B1	ENST00000544448.6	TSL:1	n.*767A>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000444966.2
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.*384A>G		3_prime_UTR	Exon 13 of 13	ENSP00000360645.4

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75727 AN: 151710 Hom.: 19242 Cov.: 30

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.514 AC: 70309 AN: 136668 AF XY: 0.511

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.716

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.489 AC: 152970 AN: 313060 Hom.: 38252 Cov.: 0 AF XY: 0.488 AC XY: 86676 AN XY: 177738

African (AFR) AF: 0.547 AC: 4902 AN: 8956

American (AMR) AF: 0.573 AC: 15742 AN: 27494

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 5905 AN: 11168

East Asian (EAS) AF: 0.715 AC: 6965 AN: 9742

South Asian (SAS) AF: 0.503 AC: 30064 AN: 59796

European-Finnish (FIN) AF: 0.434 AC: 5705 AN: 13160

Middle Eastern (MID) AF: 0.448 AC: 1265 AN: 2826

European-Non Finnish (NFE) AF: 0.456 AC: 75293 AN: 165144

Other (OTH) AF: 0.483 AC: 7129 AN: 14774

GnomAD4 genome AF: 0.499 AC: 75800 AN: 151826 Hom.: 19266 Cov.: 30 AF XY: 0.499 AC XY: 37045 AN XY: 74206

African (AFR) AF: 0.550 AC: 22778 AN: 41394

American (AMR) AF: 0.531 AC: 8108 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3648 AN: 5144

South Asian (SAS) AF: 0.507 AC: 2434 AN: 4804

European-Finnish (FIN) AF: 0.421 AC: 4453 AN: 10568

Middle Eastern (MID) AF: 0.438 AC: 127 AN: 290

European-Non Finnish (NFE) AF: 0.455 AC: 30909 AN: 67890

Other (OTH) AF: 0.505 AC: 1062 AN: 2102

Alfa AF: 0.469 Hom.: 18539

Bravo AF: 0.514

Asia WGS AF: 0.582 AC: 2025 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rafiq syndrome Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.64
DANN	Benign	0.47
PhyloP100		-4.7
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: rs4567; hg19: chr9-140003427;