chr1-46190473-C-T

Variant names:

• chr1-46190473-C-T
• rs193919335
• NM_017739.4:c.1649G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.30
• Publications: 8 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-46190473-C-T is Pathogenic according to our data. 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.

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.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 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.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1649G>A	p.Ser550Asn	missense splice_region	Exon 19 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Muscle eye brain disease (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.77		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
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs193919335; hg19: chr1-46656145;