chr22-41586091-C-G

Variant names:

• chr22-41586091-C-G
• NM_002676.3:c.190G>C

Variant summary

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

The NM_002676.3(PMM1):​c.190G>C​(p.Gly64Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PMM1 NM_002676.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

Genes affected

PMM1 (HGNC:9114): (phosphomannomutase 1) Phosphomannomutase catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins. [provided by RefSeq, Jul 2008]

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, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002676.3. 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
	PMM1	NM_002676.3	MANE Select	c.190G>C	p.Gly64Arg	missense	Exon 2 of 8	NP_002667.2	Q92871

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM1	ENST00000216259.8	TSL:1 MANE Select	c.190G>C	p.Gly64Arg	missense	Exon 2 of 8	ENSP00000216259.7	Q92871
	PMM1	ENST00000949539.1		c.424G>C	p.Gly142Arg	missense	Exon 4 of 10	ENSP00000619598.1
	PMM1	ENST00000940470.1		c.319G>C	p.Gly107Arg	missense	Exon 3 of 9	ENSP00000610529.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456512 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724528

⚠️ 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: 33054

American (AMR) AF: 0.00 AC: 0 AN: 44054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 38952

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109834

Other (OTH) AF: 0.00 AC: 0 AN: 60208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000666134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	0.79
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.54		Gain of solvent accessibility (P = 0.0097)
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.72
gMVP		0.88
Mutation Taster		=46/54	disease causing

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

hg19: chr22-41982095;