1-46188770-C-T

Variant names:

• chr1-46188770-C-T
• rs764840485
• NM_017739.4:c.*500G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001243766.2(POMGNT1):​c.2196G>A​(p.Trp732*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POMGNT1 NM_001243766.2 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.358
• 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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0227 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243766.2. 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.*500G>A		3_prime_UTR	Exon 22 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.2196G>A	p.Trp732*	stop_gained	Exon 23 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.2106G>A	p.Trp702*	stop_gained	Exon 22 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.*500G>A		3_prime_UTR	Exon 22 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.2196G>A	p.Trp732*	stop_gained	Exon 23 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.2106G>A	p.Trp702*	stop_gained	Exon 22 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243928 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460506 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726550

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000895 AC: 4 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000857 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.31	N
PhyloP100		0.36
Vest4		0.17
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=95/105	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs764840485; hg19: chr1-46654442;