9-137108423-C-T

Variant names:

• chr9-137108423-C-T
• rs34355967
• NM_016219.5:c.1932C>T

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. V644V) has been classified 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
• Publications: 5 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: ClinGen, Orphanet
• Rafiq syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	NM_016219.5	MANE Select	c.1932C>T	p.Val644Val	synonymous	Exon 13 of 13	NP_057303.2	Q9UKM7
	MAN1B1	NR_045720.2		n.1922C>T		non_coding_transcript_exon	Exon 13 of 13
	MAN1B1	NR_045721.2		n.2078C>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.1932C>T	p.Val644Val	synonymous	Exon 13 of 13	ENSP00000360645.4	Q9UKM7
	MAN1B1	ENST00000371587.9	TSL:1	n.*1609C>T		non_coding_transcript_exon	Exon 14 of 14	ENSP00000483132.2	A0A087X064
	MAN1B1	ENST00000371587.9	TSL:1	n.*1609C>T		3_prime_UTR	Exon 14 of 14	ENSP00000483132.2	A0A087X064

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

GnomAD2 exomes AF: 0.00952 AC: 2392 AN: 251300 AF XY: 0.00935

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 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

African (AFR) AF: 0.00200 AC: 67 AN: 33480

American (AMR) AF: 0.00785 AC: 351 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 274 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.0121 AC: 644 AN: 53108

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0150 AC: 16647 AN: 1111980

Other (OTH) AF: 0.00997 AC: 602 AN: 60384

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

African (AFR) AF: 0.00241 AC: 100 AN: 41548

American (AMR) AF: 0.00935 AC: 143 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1030 AN: 68026

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0116 Hom.: 26

Bravo AF: 0.00917

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Rafiq syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	MAN1B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.9
DANN	Benign	0.88
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs34355967; hg19: chr9-140002875;