chr1-46192097-C-T

Variant names:

• chr1-46192097-C-T
• rs138642840
• NM_017739.4:c.1539+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Moderate PS3 PP5_Very_Strong

The NM_017739.4(POMGNT1):​c.1539+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329689: Published functional studies demonstrate a damaging effect as c.1539+1 G>A causes read-through of intronic sequences, resulting in introduction of a premature termination codon (Yoshida et al., 2001)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: POMGNT1 NM_017739.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 7.48
• Publications: 12 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06354009 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329689: Published functional studies demonstrate a damaging effect as c.1539+1 G>A causes read-through of intronic sequences, resulting in introduction of a premature termination codon (Yoshida et al., 2001);; SCV000357985: Functional studies using targeted expression in HEK293 cells or fibroblasts from patients demonstrated that the POMGNT1 enzyme activity was significantly reduced (Yoshida et al. 2001; Vajsar et al. 2006).; SCV001448404: "At least one publication reports experimental evidence that this variant affects mRNA splicing and caused skipping of the upstream exon 17 (Predicted effect: p.Leu472_His513del, Yoshida_2001)."; SCV003761158: "In vitro functional studies provide some evidence that the c.1539+1G>A variant may impact protein function." PMID:11709191
• PP5: Variant 1-46192097-C-T is Pathogenic according to our data. Variant chr1-46192097-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56582.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.1539+1G>A		splice_donor intron	N/A	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1539+1G>A		splice_donor intron	N/A	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1539+1G>A		splice_donor intron	N/A	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.1539+1G>A		splice_donor intron	N/A	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1539+1G>A		splice_donor intron	N/A	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1539+1G>A		splice_donor intron	N/A	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000617 AC: 155 AN: 251296 AF XY: 0.000611

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 726992

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86234

European-Finnish (FIN) AF: 0.00230 AC: 123 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000326 AC: 362 AN: 1111528

Other (OTH) AF: 0.000315 AC: 19 AN: 60376

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74470

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2O (3)
2	-	-	Muscle eye brain disease (2)
2	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies (1)
1	-	-	Muscle eye brain disease;C3150412:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O;C4310704:Retinitis pigmentosa 76 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O;C3151519:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O;C3151519:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3;C4310704:Retinitis pigmentosa 76 (1)
1	-	-	Myopathy caused by variation in POMGNT1 (1)
1	-	-	POMGNT1-related disorder (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		7.5
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs138642840; hg19: chr1-46657769;