rs386834024

Variant names:

• chr1-46189457-C-A
• rs386834024
• NM_017739.4:c.1895+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-46189457-C-A
• chr1-46189457-C-G
• chr1-46189457-C-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_017739.4(POMGNT1):​c.1895+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,366 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000577451: Published functional studies demonstrate the splice defect leads to retention of intron 21 (Saredi et al., 2012)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: POMGNT1 NM_017739.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9929
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 7.53
• Publications: 4 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 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000577451: Published functional studies demonstrate the splice defect leads to retention of intron 21 (Saredi et al., 2012);; SCV000833678: Studies have shown that disruption of this splice site results in partial inclusion of intron 21 (also known as intron 25) and introduces a new termination codon (PMID: 28424332).; SCV000914412: RT-PCR experiments demonstrated that the variant affects splicing with retention of the intron between exons 21 and 22 (Saredi et al. 2012).; SCV004741883: Functional RNA studies on this variant have shown it leads to retention of intron 21 (Saredi et al. 2012. PubMed ID: 22554691).; SCV001164571: "In vitro functional studies provide some evidence that the c.1895+1G>T variant may impact protein function with abnormal splicing and reduced translation." PMID: 22554691; SCV002060325: Functional assessments of this variant are available in the literature (PMID: 22554691).; SCV006085440: The variant allele was found at a frequency of 8e-05 in 249666 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POMGNT1 causing Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, allowing no conclusion about variant significance. c.1895+1G>T has been observed in individual(s) affected with Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (example: Cummings_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28424332). no; SCV003761147: The variant was shown by RT-PCR analysis (PMID: 22554691) and muscle RNAseq of patient tissue (PMID: 28424332) to alter splicing and lead to intron retention between exons 21 and 22.
• PP5: Variant 1-46189457-C-A is Pathogenic according to our data. Variant chr1-46189457-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56593.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.1895+1G>T		splice_donor intron	N/A	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1869+27G>T		intron	N/A	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1895+1G>T		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.1895+1G>T		splice_donor intron	N/A	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1869+27G>T		intron	N/A	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1895+1G>T		splice_donor intron	N/A	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000801 AC: 20 AN: 249666 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461226 Hom.: 0 Cov.: 30 AF XY: 0.0000963 AC XY: 70 AN XY: 726838

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000672 AC: 3 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111702

Other (OTH) AF: 0.000133 AC: 8 AN: 60362

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000968 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (4)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2O (2)
2	-	-	Muscle eye brain disease (2)
2	-	-	not provided (2)
2	-	-	POMGNT1-related disorder (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (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;C4310704:Retinitis pigmentosa 76 (1)
1	-	-	Myopathy caused by variation in POMGNT1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
Splicevardb		3.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 27
DS_DL_spliceai		0.94		Position offset: 1

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

dbSNP: rs386834024;

hg19: chr1-46655129;