9-137108975-A-G

Position:

• chr9-137108975-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000371589.9(MAN1B1):​c.*384A>G variant causes a 3 prime UTR 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 ENST00000371589.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.72

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-137108975-A-G is Benign according to our data. Variant chr9-137108975-A-G is described in ClinVar as [Benign]. Clinvar id is 365984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137108975-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.*384A>G		3_prime_UTR_variant	13/13	ENST00000371589.9	NP_057303.2
MAN1B1	NR_045720.2	n.2474A>G		non_coding_transcript_exon_variant	13/13
MAN1B1	NR_045721.2	n.2630A>G		non_coding_transcript_exon_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.*384A>G		3_prime_UTR_variant	13/13	1	NM_016219.5	ENSP00000360645	P2

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

GnomAD3 exomes AF: 0.514 AC: 70309 AN: 136668 Hom.: 18564 AF XY: 0.511 AC XY: 37924 AN XY: 74210

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 SAS exome AF: 0.500

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

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.529

Gnomad4 EAS exome AF: 0.715

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.483

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

Gnomad4 AFR AF: 0.550

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.709

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.505

Alfa AF: 0.469 Hom.: 15671

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.64
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs4567; hg19: chr9-140003427;