rs41292143

Variant names:

• chr1-46192545-C-T
• rs41292143
• NM_017739.4:c.1257G>A
• POMGNT1 p.Leu419Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017739.4(POMGNT1):​c.1257G>A​(p.Leu419Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,166 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L419L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.017 (254 hom.)
• Consequence: POMGNT1 NM_017739.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.268
• Publications: 7 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-46192545-C-T is Benign according to our data. Variant chr1-46192545-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1553/152306) while in subpopulation NFE AF = 0.0185 (1258/68024). AF 95% confidence interval is 0.0176. There are 12 homozygotes in GnomAd4. There are 665 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

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.1257G>A	p.Leu419Leu	synonymous	Exon 15 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1257G>A	p.Leu419Leu	synonymous	Exon 15 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1257G>A	p.Leu419Leu	synonymous	Exon 15 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.1257G>A	p.Leu419Leu	synonymous	Exon 15 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1257G>A	p.Leu419Leu	synonymous	Exon 15 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1257G>A	p.Leu419Leu	synonymous	Exon 15 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152190 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00889 AC: 2234 AN: 251268 AF XY: 0.00885

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00755

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0168 AC: 24564 AN: 1461860 Hom.: 254 Cov.: 31 AF XY: 0.0162 AC XY: 11787 AN XY: 727230

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00344 AC: 154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00205 AC: 177 AN: 86258

European-Finnish (FIN) AF: 0.00436 AC: 233 AN: 53398

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0207 AC: 23004 AN: 1112004

Other (OTH) AF: 0.0122 AC: 738 AN: 60396

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152306 Hom.: 12 Cov.: 32 AF XY: 0.00893 AC XY: 665 AN XY: 74476

African (AFR) AF: 0.00351 AC: 146 AN: 41550

American (AMR) AF: 0.00497 AC: 76 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1258 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0136 Hom.: 6

Bravo AF: 0.00983

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0173

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2O (1)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	-	1	Muscle eye brain disease (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.67
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: rs41292143;

hg19: chr1-46658217;