Genetic Variant POMGNT1:p.Thr433Met (chr1-46192423-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_017739.4(POMGNT1):c.1298C>T(p.Thr433Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,156 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T433T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 20 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.31

Publications

5 publications found

Variant links:

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 links:

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]

TSPAN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_017739.4

BP4

Computational evidence support a benign effect (MetaRNN=0.010501802).

BP6

Variant 1-46192423-G-A is Benign according to our data. Variant chr1-46192423-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00273 (416/152282) while in subpopulation AMR AF = 0.00608 (93/15294). AF 95% confidence interval is 0.00508. There are 2 homozygotes in GnomAd4. There are 265 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_017739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POMGNT1	NM_017739.4	MANE Select	c.1298C>T	p.Thr433Met	missense	Exon 16 of 22	NP_060209.4
POMGNT1	NM_001243766.2		c.1298C>T	p.Thr433Met	missense	Exon 16 of 23	NP_001230695.2
POMGNT1	NM_001410783.1		c.1298C>T	p.Thr433Met	missense	Exon 16 of 22	NP_001397712.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.1298C>T	p.Thr433Met	missense	Exon 16 of 22	ENSP00000361052.3
POMGNT1	ENST00000371992.1	TSL:2	c.1298C>T	p.Thr433Met	missense	Exon 16 of 23	ENSP00000361060.1
POMGNT1	ENST00000692369.1		c.1298C>T	p.Thr433Met	missense	Exon 16 of 22	ENSP00000508453.1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00388

AC:

976

AN:

251242

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0182

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00126

AC:

1847

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

869

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.0138

AC:

616

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0176

AC:

942

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000138

AC:

154

AN:

1112002

Other (OTH)

AF:

0.00114

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

140

281

421

562

702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00273

AC:

416

AN:

152282

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41554

American (AMR)

AF:

0.00608

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0213

AC:

226

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000729

Hom.:

Bravo

AF:

0.00198

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00317

AC:

385

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Muscle eye brain disease (2)

Autosomal recessive limb-girdle muscular dystrophy type 2O (1)

Congenital Muscular Dystrophy, alpha-dystroglycan related (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

Uncertain

0.45

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.4

PhyloP100

9.3

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.75

MVP

0.96

MPC

0.91

ClinPred

0.026

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.68

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over