19-12666701-T-G

Variant names:

• chr19-12666701-T-G
• rs967834240
• NM_000528.4:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_000528.4(MAN2B1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.93

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]

ENSG00000269590 (HGNC:):

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 24 codons. Genomic position: 12666632. Lost 0.023 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 24	ENST00000456935.7	NP_000519.2
WDR83	NM_001099737.3	c.-448T>G		upstream_gene_variant		ENST00000418543.8	NP_001093207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.151-896A>C		intron_variant	Intron 2 of 4	4		ENSP00000472710.1
WDR83	ENST00000418543.8	c.-448T>G		upstream_gene_variant		1	NM_001099737.3	ENSP00000402653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000684 AC: 1 AN: 146180 Hom.: 0 AF XY: 0.0000127 AC XY: 1 AN XY: 78864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000936

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396534 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:2

Dec 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.48	T
PROVEAN	Benign	-0.81	N;N;.;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.075	B;.;.;.
Vest4		0.91
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);
MVP		0.90
ClinPred		0.78	D
GERP RS		3.3
Varity_R		0.97
gMVP		0.75

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: rs967834240; hg19: chr19-12777515;