1-25618219-T-A

Variant names:

• chr1-25618219-T-A
• rs746317826
• NM_020379.4:c.422T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020379.4(MAN1C1):​c.422T>A​(p.Phe141Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F141S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAN1C1 NM_020379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0975177).

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.422T>A	p.Phe141Tyr	missense	Exon 1 of 12	NP_065112.1	Q9NR34
	MAN1C1	NM_001385182.1		c.422T>A	p.Phe141Tyr	missense	Exon 1 of 13	NP_001372111.1
	MAN1C1	NM_001385183.1		c.422T>A	p.Phe141Tyr	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.422T>A	p.Phe141Tyr	missense	Exon 1 of 12	ENSP00000363452.4	Q9NR34
	MAN1C1	ENST00000899084.1		c.422T>A	p.Phe141Tyr	missense	Exon 1 of 12	ENSP00000569143.1
	MAN1C1	ENST00000929760.1		c.422T>A	p.Phe141Tyr	missense	Exon 1 of 11	ENSP00000599819.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445758 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 718162

⚠️ 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: 33092

American (AMR) AF: 0.00 AC: 0 AN: 42264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38954

South Asian (SAS) AF: 0.00 AC: 0 AN: 83716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107028

Other (OTH) AF: 0.00 AC: 0 AN: 59886

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.37
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.11
Sift	Benign	0.53	T
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.29
MutPred		0.28		Loss of sheet (P = 0.0457)
MVP		0.58
MPC		0.71
ClinPred		0.13	T
GERP RS		0.52
PromoterAI		-0.30	Neutral
Varity_R		0.054
gMVP		0.27
Mutation Taster		=96/4	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: rs746317826; hg19: chr1-25944710;