6-119189810-A-G

Position:

• chr6-119189810-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005907.4(MAN1A1):​c.1400T>C​(p.Leu467Pro) 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: 32)
• Consequence: MAN1A1 NM_005907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

MAN1A1 (HGNC:6821): (mannosidase alpha class 1A member 1) This gene encodes a class I mammalian Golgi 1,2-mannosidase which is a type II transmembrane protein. This protein catalyzes the hydrolysis of three terminal mannose residues from peptide-bound Man(9)-GlcNAc(2) oligosaccharides and belongs to family 47 of glycosyl hydrolases. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1A1	NM_005907.4	c.1400T>C	p.Leu467Pro	missense_variant	10/13	ENST00000368468.4	NP_005898.2
MAN1A1	XM_005266986.5	c.1649T>C	p.Leu550Pro	missense_variant	10/13		XP_005267043.1
MAN1A1	XM_011535833.3	c.833T>C	p.Leu278Pro	missense_variant	9/12		XP_011534135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1A1	ENST00000368468.4	c.1400T>C	p.Leu467Pro	missense_variant	10/13	2	NM_005907.4	ENSP00000357453.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.1400T>C (p.L467P) alteration is located in exon 10 (coding exon 9) of the MAN1A1 gene. This alteration results from a T to C substitution at nucleotide position 1400, causing the leucine (L) at amino acid position 467 to be replaced by a proline (P). 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	0.57
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.0090	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.82
Sift	Benign	0.046	D
Sift4G	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.98
MutPred		0.80		Gain of disorder (P = 0.011);
MVP		0.86
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-119510975;