1-25617940-G-T

Variant names:

• chr1-25617940-G-T
• rs542319846
• NM_020379.4:c.143G>T

Variant summary

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

The NM_020379.4(MAN1C1):​c.143G>T​(p.Arg48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,640 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R48S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAN1C1 NM_020379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• Publications: 0 publications found

Genes affected

MAN1C1 (HGNC:19080): (mannosidase alpha class 1C member 1) Predicted to enable mannosyl-oligosaccharide 1,2-alpha-mannosidase activity. Predicted to be involved in N-glycan processing. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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_020379.4. 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
	MAN1C1	NM_020379.4	MANE Select	c.143G>T	p.Arg48Leu	missense	Exon 1 of 12	NP_065112.1	Q9NR34
	MAN1C1	NM_001385182.1		c.143G>T	p.Arg48Leu	missense	Exon 1 of 13	NP_001372111.1
	MAN1C1	NM_001385183.1		c.143G>T	p.Arg48Leu	missense	Exon 1 of 12	NP_001372112.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN1C1	ENST00000374332.9	TSL:1 MANE Select	c.143G>T	p.Arg48Leu	missense	Exon 1 of 12	ENSP00000363452.4	Q9NR34
	MAN1C1	ENST00000899084.1		c.143G>T	p.Arg48Leu	missense	Exon 1 of 12	ENSP00000569143.1
	MAN1C1	ENST00000929760.1		c.143G>T	p.Arg48Leu	missense	Exon 1 of 11	ENSP00000599819.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000835 AC: 2 AN: 239396 AF XY: 0.00000764

Gnomad AFR exome AF: 0.0000687

Gnomad AMR exome AF: 0.0000300

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: 0.00000138 AC: 2 AN: 1454476 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723596

African (AFR) AF: 0.00 AC: 0 AN: 32604

American (AMR) AF: 0.0000454 AC: 2 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 38864

South Asian (SAS) AF: 0.00 AC: 0 AN: 85378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109430

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74426

African (AFR) AF: 0.0000482 AC: 2 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000825 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	Benign	0.32
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.64
Sift	Benign	0.052	T
Sift4G	Uncertain	0.019	D
Polyphen		0.96	D
Vest4		0.42
MutPred		0.67		Gain of helix (P = 0.0093)
MVP		0.92
MPC		1.5
ClinPred		0.48	T
GERP RS		4.0
PromoterAI		-0.024	Neutral
Varity_R		0.22
gMVP		0.60
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs542319846; hg19: chr1-25944431;