chr9-137087087-G-C

Variant names:

• chr9-137087087-G-C
• NM_016219.5:c.88G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016219.5(MAN1B1):​c.88G>C​(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A30A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10005495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 13	ENST00000371589.9	NP_057303.2
MAN1B1	XM_006716945.5	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 12		XP_006717008.1
MAN1B1	NR_045720.2	n.103G>C		non_coding_transcript_exon_variant	Exon 1 of 13
MAN1B1	NR_045721.2	n.103G>C		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 13	1	NM_016219.5	ENSP00000360645.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718918

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 42578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39196

South Asian (SAS) AF: 0.00 AC: 0 AN: 83842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107212

Other (OTH) AF: 0.0000167 AC: 1 AN: 59796

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88G>C (p.A30P) alteration is located in exon 1 (coding exon 1) of the MAN1B1 gene. This alteration results from a G to C substitution at nucleotide position 88, causing the alanine (A) at amino acid position 30 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.11
Sift	Benign	0.060	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.053	B
Vest4		0.28
MutPred		0.40		Gain of loop (P = 0.0097);
MVP		0.19
MPC		0.47
ClinPred		0.17	T
GERP RS		2.4
PromoterAI		-0.092	Neutral
Varity_R		0.073
gMVP		0.33
Mutation Taster		=89/11	polymorphism

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

hg19: chr9-139981539;