rs2292487

Variant names:

• chr1-46194623-T-C
• rs2292487
• NM_017739.4:c.681A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017739.4(POMGNT1):​c.681A>G​(p.Lys227Lys) 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 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:19
• Conservation: PhyloP100: 0.397
• Publications: 38 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 (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 VariationId is 95761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.681A>G	p.Lys227Lys	synonymous	Exon 8 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.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	ENSP00000508453.1	A0A8I5KNB7

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

GnomAD2 exomes AF: 0.355 AC: 89316 AN: 251468 AF XY: 0.358

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 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

African (AFR) AF: 0.361 AC: 12070 AN: 33480

American (AMR) AF: 0.388 AC: 17347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8042 AN: 26136

East Asian (EAS) AF: 0.157 AC: 6229 AN: 39700

South Asian (SAS) AF: 0.450 AC: 38779 AN: 86256

European-Finnish (FIN) AF: 0.395 AC: 21087 AN: 53418

Middle Eastern (MID) AF: 0.381 AC: 2197 AN: 5768

European-Non Finnish (NFE) AF: 0.352 AC: 391774 AN: 1112008

Other (OTH) AF: 0.342 AC: 20682 AN: 60396

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

African (AFR) AF: 0.350 AC: 14509 AN: 41478

American (AMR) AF: 0.362 AC: 5541 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1087 AN: 3468

East Asian (EAS) AF: 0.160 AC: 827 AN: 5174

South Asian (SAS) AF: 0.435 AC: 2096 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4060 AN: 10572

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23994 AN: 67964

Other (OTH) AF: 0.353 AC: 745 AN: 2112

Alfa AF: 0.353 Hom.: 10884

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2O (2)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	-	1	Muscle eye brain disease (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (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	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 76 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
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
PhyloP100		0.40
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
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

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