rs199592616

Variant names:

• chr4-102664676-A-G
• rs199592616
• NM_005908.4:c.1485+9T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-102664676-A-G
• chr4-102664676-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005908.4(MANBA):​c.1485+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,605,588 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANBA Gene-Disease associations (from GenCC):

• beta-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-102664676-A-G is Benign according to our data. Variant chr4-102664676-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000519 (79/152344) while in subpopulation SAS AF = 0.00331 (16/4832). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005908.4. 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
	MANBA	NM_005908.4	MANE Select	c.1485+9T>C		intron	N/A	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.1485+9T>C		intron	N/A	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.1623+9T>C		intron	N/A	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.1584+9T>C		intron	N/A	ENSP00000624485.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00115 AC: 288 AN: 251248 AF XY: 0.00141

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000634 AC: 921 AN: 1453244 Hom.: 6 Cov.: 29 AF XY: 0.000860 AC XY: 622 AN XY: 723594

African (AFR) AF: 0.000781 AC: 26 AN: 33270

American (AMR) AF: 0.000917 AC: 41 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00674 AC: 580 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5756

European-Non Finnish (NFE) AF: 0.000144 AC: 159 AN: 1104138

Other (OTH) AF: 0.00111 AC: 67 AN: 60140

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74504

African (AFR) AF: 0.000481 AC: 20 AN: 41568

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Beta-D-mannosidosis (2)
-	-	1	MANBA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		2.6
Mutation Taster		=100/0	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

dbSNP: rs199592616; hg19: chr4-103585833;