9-137108423-C-T

Position:

• chr9-137108423-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_016219.5(MAN1B1):​c.1932C>T​(p.Val644Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,816 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (153 hom.)
• Consequence: MAN1B1 NM_016219.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.127

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 9-137108423-C-T is Benign according to our data. Variant chr9-137108423-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.127 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00965 (1469/152278) while in subpopulation NFE AF= 0.0151 (1030/68026). AF 95% confidence interval is 0.0144. There are 9 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.1932C>T	p.Val644Val	synonymous_variant	13/13	ENST00000371589.9	NP_057303.2
MAN1B1	NR_045720.2	n.1922C>T		non_coding_transcript_exon_variant	13/13
MAN1B1	NR_045721.2	n.2078C>T		non_coding_transcript_exon_variant	14/14
MAN1B1	XM_006716945.5	c.*461C>T		downstream_gene_variant			XP_006717008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.1932C>T	p.Val644Val	synonymous_variant	13/13	1	NM_016219.5	ENSP00000360645.4

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1469 AN: 152160 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00952 AC: 2392 AN: 251300 Hom.: 20 AF XY: 0.00935 AC XY: 1270 AN XY: 135850

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.0127 AC: 18611 AN: 1461538 Hom.: 153 Cov.: 32 AF XY: 0.0123 AC XY: 8946 AN XY: 727080

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.00965 AC: 1469 AN: 152278 Hom.: 9 Cov.: 33 AF XY: 0.00907 AC XY: 675 AN XY: 74462

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00950 Hom.: 7

Bravo AF: 0.00917

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rafiq syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MAN1B1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 11, 2015

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2016

This alteration is classified as 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. -

MAN1B1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.9
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs34355967; hg19: chr9-140002875;