rs570143986

Variant names:

• chr6-95596746-C-G
• rs570143986
• NM_024641.4:c.554C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024641.4(MANEA):​c.554C>G​(p.Ala185Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,578,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MANEA NM_024641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

Genes affected

MANEA (HGNC:21072): (mannosidase endo-alpha) N-glycosylation of proteins is initiated in the endoplasmic reticulum (ER) by the transfer of the preassembled oligosaccharide glucose-3-mannose-9-N-acetylglucosamine-2 from dolichyl pyrophosphate to acceptor sites on the target protein by an oligosaccharyltransferase complex. This core oligosaccharide is sequentially processed by several ER glycosidases and by an endomannosidase (E.C. 3.2.1.130), such as MANEA, in the Golgi. MANEA catalyzes the release of mono-, di-, and triglucosylmannose oligosaccharides by cleaving the alpha-1,2-mannosidic bond that links them to high-mannose glycans (Hamilton et al., 2005 [PubMed 15677381]).[supplied by OMIM, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024641.4. 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
	MANEA	NM_024641.4	MANE Select	c.554C>G	p.Ala185Gly	missense	Exon 3 of 5	NP_078917.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANEA	ENST00000358812.9	TSL:1 MANE Select	c.554C>G	p.Ala185Gly	missense	Exon 3 of 5	ENSP00000351669.4	Q5SRI9
	MANEA	ENST00000682663.1		c.554C>G	p.Ala185Gly	missense	Exon 3 of 5	ENSP00000507267.1	Q5SRI9
	MANEA	ENST00000684753.1		c.554C>G	p.Ala185Gly	missense	Exon 3 of 5	ENSP00000506887.1	Q5SRI9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250758 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000140 AC: 2 AN: 1426652 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 711950

African (AFR) AF: 0.0000610 AC: 2 AN: 32780

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 85322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080526

Other (OTH) AF: 0.00 AC: 0 AN: 59200

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74386

African (AFR) AF: 0.0000482 AC: 2 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0042	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.026	D
Polyphen		0.97	D
Vest4		0.74
MutPred		0.25		Loss of catalytic residue at A185 (P = 0.0587)
MVP		0.43
MPC		0.21
ClinPred		0.93	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.78
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs570143986; hg19: chr6-96044622;