1-25686440-A-G

Variant names:

• chr1-25686440-A-G
• rs2046232062
• NM_020379.4:c.541A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020379.4(MAN1C1):​c.541A>G​(p.Met181Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN1C1 NM_020379.4 missense, splice_region
• Scores: Splicing: ADA: 0.4255
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.02
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.541A>G	p.Met181Val	missense splice_region	Exon 2 of 12	NP_065112.1	Q9NR34
	MAN1C1	NM_001385182.1		c.541A>G	p.Met181Val	missense splice_region	Exon 2 of 13	NP_001372111.1
	MAN1C1	NM_001385183.1		c.541A>G	p.Met181Val	missense splice_region	Exon 2 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.541A>G	p.Met181Val	missense splice_region	Exon 2 of 12	ENSP00000363452.4	Q9NR34
	MAN1C1	ENST00000899084.1		c.541A>G	p.Met181Val	missense splice_region	Exon 2 of 12	ENSP00000569143.1
	MAN1C1	ENST00000929760.1		c.541A>G	p.Met181Val	missense splice_region	Exon 2 of 11	ENSP00000599819.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.61		Loss of disorder (P = 0.0511)
MVP		0.67
MPC		1.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.83
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.43
dbscSNV1_RF	Benign	0.61
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: rs2046232062; hg19: chr1-26012931;