rs150576537

Variant names:

• chr1-46196784-C-T
• rs150576537
• NM_017739.4:c.301G>A
• POMGNT1 p.Val101Ile

Your query was ambiguous. Multiple possible variants found:

• chr1-46196784-C-T
• chr1-46196784-C-A
• chr1-46196784-C-G

Variant summary

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

The NM_017739.4(POMGNT1):​c.301G>A​(p.Val101Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,190 control chromosomes in the GnomAD database, including 34 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).

• Frequency:
  • Genomes: 𝑓 0.0024 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (28 hom.)
• Consequence: POMGNT1 NM_017739.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 4.44
• Publications: 11 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]

POMGNT1 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2O

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P
• muscle-eye-brain disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women's Health
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
• myopathy caused by variation in POMGNT1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 76

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_017739.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0067639947).
• BP6: Variant 1-46196784-C-T is Benign according to our data. Variant chr1-46196784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95759.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00245 (373/152348) while in subpopulation AMR AF = 0.00327 (50/15310). AF 95% confidence interval is 0.00254. There are 6 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.301G>A	p.Val101Ile	missense	Exon 4 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001243766.2		c.301G>A	p.Val101Ile	missense	Exon 4 of 23	NP_001230695.2	Q8WZA1-2
	POMGNT1	NM_001410783.1		c.301G>A	p.Val101Ile	missense	Exon 4 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.301G>A	p.Val101Ile	missense	Exon 4 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.301G>A	p.Val101Ile	missense	Exon 4 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.301G>A	p.Val101Ile	missense	Exon 4 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152230 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00314 AC: 789 AN: 251406 AF XY: 0.00300

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00212 AC: 3098 AN: 1461842 Hom.: 28 Cov.: 33 AF XY: 0.00210 AC XY: 1526 AN XY: 727220

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 1176 AN: 26136

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

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53374

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00137 AC: 1523 AN: 1112008

Other (OTH) AF: 0.00406 AC: 245 AN: 60394

GnomAD4 genome AF: 0.00245 AC: 373 AN: 152348 Hom.: 6 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74502

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.00327 AC: 50 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00361 Hom.: 10

Bravo AF: 0.00234

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (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 intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O (1)
-	-	1	POMGNT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.82
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.51	N
PhyloP100		4.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.088
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.15
gMVP		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150576537;

hg19: chr1-46662456;

COSMIC: COSV64339613;

COSMIC: COSV64339613;