1-46192127-C-T

Variant names:

• chr1-46192127-C-T
• rs17102066
• NM_017739.4:c.1510G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001243766.2(POMGNT1):​c.1510G>A​(p.Val504Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,614,108 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V504F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: POMGNT1 NM_001243766.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 3.76
• Publications: 4 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 -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001243766.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.013732314).
• BP6: Variant 1-46192127-C-T is Benign according to our data. Variant chr1-46192127-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281057.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00243 (370/152272) while in subpopulation AFR AF = 0.00843 (350/41540). AF 95% confidence interval is 0.0077. There are 2 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	NM_017739.4	MANE Select	c.1510G>A	p.Val504Ile	missense	Exon 17 of 22	NP_060209.4
	POMGNT1	NM_001243766.2		c.1510G>A	p.Val504Ile	missense	Exon 17 of 23	NP_001230695.2
	POMGNT1	NM_001410783.1		c.1510G>A	p.Val504Ile	missense	Exon 17 of 22	NP_001397712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.1510G>A	p.Val504Ile	missense	Exon 17 of 22	ENSP00000361052.3
	POMGNT1	ENST00000371992.1	TSL:2	c.1510G>A	p.Val504Ile	missense	Exon 17 of 23	ENSP00000361060.1
	POMGNT1	ENST00000692369.1		c.1510G>A	p.Val504Ile	missense	Exon 17 of 22	ENSP00000508453.1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152154 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251454 AF XY: 0.000714

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1461836 Hom.: 1 Cov.: 31 AF XY: 0.000224 AC XY: 163 AN XY: 727224

African (AFR) AF: 0.00804 AC: 269 AN: 33478

American (AMR) AF: 0.00313 AC: 140 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111960

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152272 Hom.: 2 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74460

African (AFR) AF: 0.00843 AC: 350 AN: 41540

American (AMR) AF: 0.00105 AC: 16 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000935 Hom.: 1

Bravo AF: 0.00296

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00113 AC: 137

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	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 brain and eye anomalies), type A3 (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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.21
Sift	Benign	0.29	T
Sift4G	Benign	0.48	T
Polyphen		0.049	B
Vest4		0.18
MVP		0.55
MPC		0.20
ClinPred		0.0062	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.19
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

Other links and lift over

dbSNP: rs17102066; hg19: chr1-46657799; COSMIC: COSV107458776; COSMIC: COSV107458776;