NM_001113482.2:c.399G>T

Variant names:

• chr1-37794581-G-T
• NM_001113482.2:c.399G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001113482.2(MANEAL):​c.399G>T​(p.Trp133Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MANEAL NM_001113482.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.82

Genes affected

MANEAL (HGNC:26452): (mannosidase endo-alpha like) Predicted to enable alpha-mannosidase activity. Predicted to be located in Golgi membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANEAL	NM_001113482.2	c.399G>T	p.Trp133Cys	missense_variant	Exon 1 of 4	ENST00000373045.11	NP_001106954.1
MANEAL	NM_001031740.3	c.399G>T	p.Trp133Cys	missense_variant	Exon 1 of 4		NP_001026910.1
MANEAL	XM_005270510.4	c.399G>T	p.Trp133Cys	missense_variant	Exon 1 of 3		XP_005270567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANEAL	ENST00000373045.11	c.399G>T	p.Trp133Cys	missense_variant	Exon 1 of 4	1	NM_001113482.2	ENSP00000362136.6
MANEAL	ENST00000397631.7	c.399G>T	p.Trp133Cys	missense_variant	Exon 1 of 4	1		ENSP00000380755.3
MANEAL	ENST00000532512.1	c.99G>T	p.Trp33Cys	missense_variant	Exon 1 of 3	4		ENSP00000432567.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.399G>T (p.W133C) alteration is located in exon 1 (coding exon 1) of the MANEAL gene. This alteration results from a G to T substitution at nucleotide position 399, causing the tryptophan (W) at amino acid position 133 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.037	D
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;B;.
Vest4		0.92
MutPred		0.53		Gain of disorder (P = 0.1223);Gain of disorder (P = 0.1223);.;
MVP		0.15
MPC		2.8
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-38260253;