1-46190473-C-T

Position:

• chr1-46190473-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_017739.4(POMGNT1):​c.1649G>A​(p.Ser550Asn) 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S550G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POMGNT1 NM_017739.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.30

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]

POMGNT1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 13) in uniprot entity PMGT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_017739.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-46190473-C-T is Pathogenic according to our data. Variant chr1-46190473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46190473-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46190473-C-T is described in Lovd as [Pathogenic]. Variant chr1-46190473-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4	c.1649G>A	p.Ser550Asn	missense_variant, splice_region_variant	19/22	ENST00000371984.8	NP_060209.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8	c.1649G>A	p.Ser550Asn	missense_variant, splice_region_variant	19/22	1	NM_017739.4	ENSP00000361052.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2023	- -

Muscle eye brain disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Jun 25, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.17
Sift	Benign	0.17	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0010	B;.
Vest4		0.33
MutPred		0.77		Loss of phosphorylation at S550 (P = 0.0419);Loss of phosphorylation at S550 (P = 0.0419);
MVP		0.82
MPC		0.24
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193919335; hg19: chr1-46656145;