1-46189989-A-C

Variant names:

• chr1-46189989-A-C
• NM_017739.4:c.1650T>G
• POMGNT1 p.Ser550Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_017739.4(POMGNT1):​c.1650T>G​(p.Ser550Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S550N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POMGNT1 NM_017739.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001499
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-46190473-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16273957).

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.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 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.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1650T>G	p.Ser550Arg	missense splice_region	Exon 20 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	5.9
DANN	Benign	0.93
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.095	N
PhyloP100		0.039
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.16
Sift	Benign	0.31	T
Sift4G	Benign	0.69	T
Varity_R		0.27
gMVP		0.72
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.048
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: chr1-46655661;