rs75639549

chr9-137106299-G-Achr9-137106299-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016219.5(MAN1B1):c.1429G>A(p.Gly477Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,553,478 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (3 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.83

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 (MetaRNN=0.010476381).
• BP6: Variant 9-137106299-G-A is Benign according to our data. Variant chr9-137106299-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137106299-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (640/152312) while in subpopulation AFR AF= 0.0144 (599/41570). AF 95% confidence interval is 0.0135. There are 5 homozygotes in gnomad4. There are 297 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1B1	NM_016219.5	c.1429G>A	p.Gly477Arg	missense_variant	9/13	ENST00000371589.9
MAN1B1	XM_006716945.5	c.1429G>A	p.Gly477Arg	missense_variant	9/12
MAN1B1	NR_045720.2	n.1444G>A		non_coding_transcript_exon_variant	9/13
MAN1B1	NR_045721.2	n.1575G>A		non_coding_transcript_exon_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9	c.1429G>A	p.Gly477Arg	missense_variant	9/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152194 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00107 AC: 170 AN: 159044 Hom.: 0 AF XY: 0.000901 AC XY: 76 AN XY: 84320

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000805

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000588 AC: 824 AN: 1401166 Hom.: 3 Cov.: 32 AF XY: 0.000548 AC XY: 379 AN XY: 691422

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.0000879

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152312 Hom.: 5 Cov.: 34 AF XY: 0.00399 AC XY: 297 AN XY: 74472

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000733 Hom.: 1

Bravo AF: 0.00478

ESP6500AA AF: 0.0109 AC: 47

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000946 AC: 103

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MAN1B1: BS1, BS2 -

Rafiq syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.041	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.56		Gain of solvent accessibility (P = 0.0014);.;
MVP		0.96
MPC		0.47
ClinPred		0.030	T
GERP RS		4.1
Varity_R		0.77
gMVP		0.77

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: rs75639549; hg19: chr9-140000751; COSMIC: COSV65371832; COSMIC: COSV65371832;