1-46194866-C-G

Variant names:

• chr1-46194866-C-G
• NM_017739.4:c.630G>C
• POMGNT1 p.Trp210Cys

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_017739.4(POMGNT1):​c.630G>C​(p.Trp210Cys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W210R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POMGNT1 NM_017739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 0 publications found

Genes affected

POMGNT1 (HGNC:19139): (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-)) This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]

TSPAN1 (HGNC:20657): (tetraspanin 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_017739.4 (POMGNT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017739.4. 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
	POMGNT1	NM_017739.4	MANE Select	c.630G>C	p.Trp210Cys	missense	Exon 7 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.630G>C	p.Trp210Cys	missense	Exon 7 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.630G>C	p.Trp210Cys	missense	Exon 7 of 22	NP_001397712.1	A0A8I5KNB7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.630G>C	p.Trp210Cys	missense	Exon 7 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.630G>C	p.Trp210Cys	missense	Exon 7 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.630G>C	p.Trp210Cys	missense	Exon 7 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-46660538;