rs74374973

Variant names:

• chr1-46189973-C-T
• rs74374973
• NM_017739.4:c.1666G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017739.4(POMGNT1):​c.1666G>A​(p.Asp556Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,614,096 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (114 hom.)
• Consequence: POMGNT1 NM_017739.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:15
• Conservation: PhyloP100: 5.83
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010585457).
• BP6: Variant 1-46189973-C-T is Benign according to our data. Variant chr1-46189973-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3997.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00956 (1457/152344) while in subpopulation AMR AF = 0.0145 (222/15306). AF 95% confidence interval is 0.0129. There are 6 homozygotes in GnomAd4. There are 693 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1666G>A	p.Asp556Asn	missense	Exon 20 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.1666G>A	p.Asp556Asn	missense	Exon 20 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.1666G>A	p.Asp556Asn	missense	Exon 20 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.1666G>A	p.Asp556Asn	missense	Exon 20 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.1666G>A	p.Asp556Asn	missense	Exon 20 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.1666G>A	p.Asp556Asn	missense	Exon 20 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1456 AN: 152226 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00997 AC: 2503 AN: 251014 AF XY: 0.00972

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00877

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0118 AC: 17243 AN: 1461752 Hom.: 114 Cov.: 33 AF XY: 0.0114 AC XY: 8314 AN XY: 727154

African (AFR) AF: 0.00185 AC: 62 AN: 33478

American (AMR) AF: 0.00946 AC: 423 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 836 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86184

European-Finnish (FIN) AF: 0.0155 AC: 826 AN: 53414

Middle Eastern (MID) AF: 0.00712 AC: 41 AN: 5760

European-Non Finnish (NFE) AF: 0.0128 AC: 14196 AN: 1111984

Other (OTH) AF: 0.0120 AC: 724 AN: 60396

GnomAD4 genome AF: 0.00956 AC: 1457 AN: 152344 Hom.: 6 Cov.: 32 AF XY: 0.00930 AC XY: 693 AN XY: 74486

African (AFR) AF: 0.00257 AC: 107 AN: 41574

American (AMR) AF: 0.0145 AC: 222 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 114 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0157 AC: 167 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 806 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0114 Hom.: 37

Bravo AF: 0.00983

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.00893 AC: 1084

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
1	1	1	Autosomal recessive limb-girdle muscular dystrophy type 2O (3)
-	-	2	Muscle eye brain disease (2)
-	1	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (2)
-	-	2	not provided (2)
-	1	-	Congenital Muscular Dystrophy, alpha-dystroglycan related (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	Retinitis pigmentosa 76 (1)
-	-	1	Structural eye disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.0089	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.48
Sift	Benign	0.046	D
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.64
MVP		0.92
MPC		0.42
ClinPred		0.0078	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.64
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs74374973; hg19: chr1-46655645; COSMIC: COSV105290116; COSMIC: COSV105290116;