9-137086790-T-G

Variant names:

• chr9-137086790-T-G
• rs1401557
• ENST00000596585.3:n.28A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000596585.3(MAN1B1-DT):​n.28A>C 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 0.998 in 152,394 control chromosomes in the GnomAD database, including 75,902 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 1.0 (75902 hom., cov: 37)
  • Exomes 𝑓: 1.0 (271696 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAN1B1-DT ENST00000596585.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.55
• Publications: 0 publications found

Genes affected

MAN1B1-DT (HGNC:48715): (MAN1B1 divergent transcript)

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.-210T>G		upstream_gene_variant		ENST00000371589.9	NP_057303.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.-210T>G		upstream_gene_variant		1	NM_016219.5	ENSP00000360645.4

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151980 AN: 152276 Hom.: 75843 Cov.: 37

Gnomad AFR AF: 0.993

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.999

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 1.00 AC: 543548 AN: 543708 Hom.: 271696 Cov.: 4 AF XY: 1.00 AC XY: 294257 AN XY: 294328

African (AFR) AF: 0.993 AC: 15403 AN: 15516

American (AMR) AF: 1.00 AC: 33424 AN: 33436

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 19298 AN: 19298

East Asian (EAS) AF: 1.00 AC: 31996 AN: 31996

South Asian (SAS) AF: 1.00 AC: 60897 AN: 60900

European-Finnish (FIN) AF: 1.00 AC: 32736 AN: 32736

Middle Eastern (MID) AF: 1.00 AC: 3599 AN: 3600

European-Non Finnish (NFE) AF: 1.00 AC: 316019 AN: 316030

Other (OTH) AF: 0.999 AC: 30176 AN: 30196

GnomAD4 genome AF: 0.998 AC: 152099 AN: 152394 Hom.: 75902 Cov.: 37 AF XY: 0.998 AC XY: 74385 AN XY: 74518

African (AFR) AF: 0.993 AC: 41316 AN: 41596

American (AMR) AF: 0.999 AC: 15305 AN: 15314

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4834 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10632 AN: 10632

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68038 AN: 68042

Other (OTH) AF: 0.999 AC: 2114 AN: 2116

Alfa AF: 0.999 Hom.: 3916

Bravo AF: 0.998

Asia WGS AF: 0.999 AC: 3475 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

- -

Jul 27, 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	1.3
DANN	Benign	0.36
PhyloP100		-1.6
PromoterAI		-0.032	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1401557; hg19: chr9-139981242;