rs139435774

Variant names:

• chr19-12657039-C-A
• rs139435774
• NM_000528.4:c.1437G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-12657039-C-A
• chr19-12657039-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000528.4(MAN2B1):​c.1437G>T​(p.Ala479Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,610,616 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A479A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: MAN2B1 NM_000528.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.44
• Publications: 0 publications found

Genes affected

MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

MAN2B1 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant 19-12657039-C-A is Benign according to our data. Variant chr19-12657039-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527128.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000528.4. 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
	MAN2B1	NM_000528.4	MANE Select	c.1437G>T	p.Ala479Ala	synonymous	Exon 12 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.1440G>T	p.Ala480Ala	synonymous	Exon 12 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.1434G>T	p.Ala478Ala	synonymous	Exon 12 of 24	NP_001166969.1	O00754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.1437G>T	p.Ala479Ala	synonymous	Exon 12 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.1434G>T	p.Ala478Ala	synonymous	Exon 12 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.1440G>T	p.Ala480Ala	synonymous	Exon 12 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000535 AC: 132 AN: 246818 AF XY: 0.000507

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000913

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00104 AC: 1515 AN: 1458436 Hom.: 4 Cov.: 31 AF XY: 0.00102 AC XY: 739 AN XY: 725602

African (AFR) AF: 0.000209 AC: 7 AN: 33432

American (AMR) AF: 0.000538 AC: 24 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86048

European-Finnish (FIN) AF: 0.000154 AC: 8 AN: 51780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00124 AC: 1378 AN: 1110748

Other (OTH) AF: 0.00116 AC: 70 AN: 60320

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74328

African (AFR) AF: 0.0000965 AC: 4 AN: 41430

American (AMR) AF: 0.000916 AC: 14 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000353 Hom.: 0

Bravo AF: 0.000706

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	Deficiency of alpha-mannosidase (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		-1.4

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: rs139435774; hg19: chr19-12767853;