rs2292487

Positions:

• chr1-46194623-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017739.4(POMGNT1):​c.681A>G​(p.Lys227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,968 control chromosomes in the GnomAD database, including 103,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K227?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.35 (9438 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93734 hom.)
• Consequence: POMGNT1 NM_017739.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.397

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029520392).
• BP6: Variant 1-46194623-T-C is Benign according to our data. Variant chr1-46194623-T-C is described in ClinVar as [Benign]. Clinvar id is 95761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46194623-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.397 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMGNT1	NM_017739.4	c.681A>G	p.Lys227=	synonymous_variant	8/22	ENST00000371984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT1	ENST00000371984.8	c.681A>G	p.Lys227=	synonymous_variant	8/22	1	NM_017739.4	P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53060 AN: 151964 Hom.: 9428 Cov.: 33

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.350

GnomAD3 exomes AF: 0.355 AC: 89316 AN: 251468 Hom.: 16649 AF XY: 0.358 AC XY: 48697 AN XY: 135914

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.354 AC: 518207 AN: 1461886 Hom.: 93734 Cov.: 95 AF XY: 0.358 AC XY: 260087 AN XY: 727244

Gnomad4 AFR exome AF: 0.361

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.349 AC: 53131 AN: 152082 Hom.: 9438 Cov.: 33 AF XY: 0.351 AC XY: 26109 AN XY: 74354

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.353

Alfa AF: 0.356 Hom.: 8045

Bravo AF: 0.343

TwinsUK AF: 0.340 AC: 1260

ALSPAC AF: 0.348 AC: 1342

ESP6500AA AF: 0.351 AC: 1548

ESP6500EA AF: 0.349 AC: 3000

ExAC AF: 0.355 AC: 43071

Asia WGS AF: 0.288 AC: 1002 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Lys227Lys in exon 8 of POMGNT1: This variant is not expected to have clinical significance because it has been identified in 35% (3000/8600) of European Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs2292487). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2O Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

Retinitis pigmentosa 76 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Muscle eye brain disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.97
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.048
Sift	Uncertain	0.018	D
Sift4G	Benign	0.19	T
Vest4		0.031
ClinPred		0.011	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292487; hg19: chr1-46660295; COSMIC: COSV64339346; COSMIC: COSV64339346;