6-95604872-A-G

Position:

• chr6-95604872-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024641.4(MANEA):​c.700A>G​(p.Met234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,320,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M234T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MANEA NM_024641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08071458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANEA	NM_024641.4	c.700A>G	p.Met234Val	missense_variant	4/5	ENST00000358812.9
MANEA	XM_005267147.4	c.700A>G	p.Met234Val	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANEA	ENST00000358812.9	c.700A>G	p.Met234Val	missense_variant	4/5	1	NM_024641.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.57e-7 AC: 1 AN: 1320962 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 657892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.81e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.53
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.26
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.049	B
Vest4		0.25
MutPred		0.17		Gain of ubiquitination at K236 (P = 0.0978);
MVP		0.56
MPC		0.14
ClinPred		0.19	T
GERP RS		4.8
Varity_R		0.24
gMVP		0.78

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: rs746149549; hg19: chr6-96052748;