chr1-46197752-T-C

Variant names:

• chr1-46197752-T-C
• rs766907690
• NM_017739.4:c.70A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001290129.3(POMGNT1):​c.-239A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POMGNT1 NM_001290129.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.77
• Publications: 0 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: Orphanet, G2P, Ambry Genetics
• muscle-eye-brain disease

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

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

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

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18503538).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290129.3. 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.70A>G	p.Thr24Ala	missense	Exon 2 of 22	NP_060209.4	Q8WZA1-1
	POMGNT1	NM_001290129.3		c.-239A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 24	NP_001277058.2
	POMGNT1	NM_001438691.1		c.-239A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001425620.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.70A>G	p.Thr24Ala	missense	Exon 2 of 22	ENSP00000361052.3	Q8WZA1-1
	POMGNT1	ENST00000371992.1	TSL:2	c.70A>G	p.Thr24Ala	missense	Exon 2 of 23	ENSP00000361060.1	Q8WZA1-2
	POMGNT1	ENST00000692369.1		c.70A>G	p.Thr24Ala	missense	Exon 2 of 22	ENSP00000508453.1	A0A8I5KNB7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.22	N
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.27
Sift	Benign	0.45	T
Sift4G	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.33		Loss of sheet (P = 3e-04)
MVP		0.67
MPC		0.24
ClinPred		0.78	D
GERP RS		4.3
PromoterAI		-0.0031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.073
gMVP		0.53
Mutation Taster		=78/22	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: rs766907690; hg19: chr1-46663424;