1-46197784-A-T

Variant names:

• chr1-46197784-A-T
• rs377724143
• NM_017739.4:c.38T>A

Variant summary

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

The NM_017739.4(POMGNT1):​c.38T>A​(p.Phe13Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F13S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POMGNT1 NM_017739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03
• Publications: 2 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: G2P, Ambry Genetics, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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: STRONG 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: 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=0.15095142).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	NM_017739.4	MANE Select	c.38T>A	p.Phe13Tyr	missense	Exon 2 of 22	NP_060209.4
	POMGNT1	NM_001290129.3		c.-271T>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 24	NP_001277058.2
	POMGNT1	NM_001438691.1		c.-271T>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001425620.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.38T>A	p.Phe13Tyr	missense	Exon 2 of 22	ENSP00000361052.3
	POMGNT1	ENST00000371992.1	TSL:2	c.38T>A	p.Phe13Tyr	missense	Exon 2 of 23	ENSP00000361060.1
	POMGNT1	ENST00000692369.1		c.38T>A	p.Phe13Tyr	missense	Exon 2 of 22	ENSP00000508453.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251404 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

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

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.23
Sift	Benign	0.28	T
Sift4G	Benign	0.40	T
Polyphen		0.0020	B
Vest4		0.34
MutPred		0.21		Gain of disorder (P = 0.1102)
MVP		0.68
MPC		0.29
ClinPred		0.19	T
GERP RS		4.2
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.50
Mutation Taster		=82/18	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: rs377724143; hg19: chr1-46663456;