NM_016219.5:c.328+233C>T

Variant names:

• chr9-137088416-C-T
• rs3750518
• NM_016219.5:c.328+233C>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.328+233C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,564,906 control chromosomes in the GnomAD database, including 128,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14147 hom., cov: 33)
  • Exomes 𝑓: 0.40 (114192 hom.)
• Consequence: MAN1B1 NM_016219.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.514
• Publications: 9 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 (BayesDel_noAF=-0.91).
• BP6: Variant 9-137088416-C-T is Benign according to our data. Variant chr9-137088416-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.328+233C>T		intron_variant	Intron 2 of 12	ENST00000371589.9	NP_057303.2
MAN1B1	NR_045720.2	n.343+233C>T		intron_variant	Intron 2 of 12
MAN1B1	NR_045721.2	n.474+18C>T		intron_variant	Intron 3 of 13
MAN1B1	XM_006716945.5	c.328+233C>T		intron_variant	Intron 2 of 11		XP_006717008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.328+233C>T		intron_variant	Intron 2 of 12	1	NM_016219.5	ENSP00000360645.4

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64795 AN: 152014 Hom.: 14130 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.439 AC: 101544 AN: 231338 AF XY: 0.434

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.397 AC: 561156 AN: 1412774 Hom.: 114192 Cov.: 36 AF XY: 0.399 AC XY: 280425 AN XY: 702740

African (AFR) AF: 0.466 AC: 15301 AN: 32838

American (AMR) AF: 0.490 AC: 21420 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 12052 AN: 25142

East Asian (EAS) AF: 0.644 AC: 23713 AN: 36816

South Asian (SAS) AF: 0.455 AC: 38702 AN: 85080

European-Finnish (FIN) AF: 0.377 AC: 12997 AN: 34464

Middle Eastern (MID) AF: 0.382 AC: 2142 AN: 5612

European-Non Finnish (NFE) AF: 0.377 AC: 410752 AN: 1090826

Other (OTH) AF: 0.413 AC: 24077 AN: 58266

GnomAD4 genome AF: 0.426 AC: 64852 AN: 152132 Hom.: 14147 Cov.: 33 AF XY: 0.427 AC XY: 31735 AN XY: 74372

African (AFR) AF: 0.473 AC: 19606 AN: 41494

American (AMR) AF: 0.454 AC: 6938 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1737 AN: 3472

East Asian (EAS) AF: 0.645 AC: 3348 AN: 5188

South Asian (SAS) AF: 0.452 AC: 2179 AN: 4824

European-Finnish (FIN) AF: 0.367 AC: 3874 AN: 10564

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25752 AN: 68000

Other (OTH) AF: 0.446 AC: 941 AN: 2112

Alfa AF: 0.421 Hom.: 12723

Bravo AF: 0.440

Asia WGS AF: 0.534 AC: 1856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.69
DANN	Benign	0.59
PhyloP100		-0.51
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: rs3750518; hg19: chr9-139982868; COSMIC: COSV64306322; COSMIC: COSV64306322;