rs764809782

Variant names:

• chr1-46196017-C-G
• rs764809782
• NM_017739.4:c.415G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-46196017-C-G
• chr1-46196017-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000371984.8(POMGNT1):​c.415G>C​(p.Ala139Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POMGNT1 ENST00000371984.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.28
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371984.8. 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.415G>C	p.Ala139Pro	missense	Exon 5 of 22	NP_060209.4
	POMGNT1	NM_001243766.2		c.415G>C	p.Ala139Pro	missense	Exon 5 of 23	NP_001230695.2
	POMGNT1	NM_001410783.1		c.415G>C	p.Ala139Pro	missense	Exon 5 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.415G>C	p.Ala139Pro	missense	Exon 5 of 22	ENSP00000361052.3
	POMGNT1	ENST00000371992.1	TSL:2	c.415G>C	p.Ala139Pro	missense	Exon 5 of 23	ENSP00000361060.1
	POMGNT1	ENST00000692369.1		c.415G>C	p.Ala139Pro	missense	Exon 5 of 22	ENSP00000508453.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

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: 53330

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Muscle eye brain disease (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.66
Sift	Benign	0.055	T
Sift4G	Uncertain	0.012	D
Polyphen		0.86	P
Vest4		0.89
MutPred		0.57		Loss of MoRF binding (P = 0.0651)
MVP		0.93
MPC		0.92
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.82
Mutation Taster		=22/78	disease causing

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: rs764809782; hg19: chr1-46661689;