chr1-46190473-C-G

Variant names:

• chr1-46190473-C-G
• NM_017739.4:c.1649G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_017739.4(POMGNT1):​c.1649G>C​(p.Ser550Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. S550N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POMGNT1 NM_017739.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 13) in uniprot entity PMGT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_017739.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-46190473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMGNT1	NM_017739.4	c.1649G>C	p.Ser550Thr	missense_variant, splice_region_variant	Exon 19 of 22	ENST00000371984.8	NP_060209.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8	c.1649G>C	p.Ser550Thr	missense_variant, splice_region_variant	Exon 19 of 22	1	NM_017739.4	ENSP00000361052.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.20
Sift	Benign	0.37	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0040	B;.
Vest4		0.26
MutPred		0.52		Loss of disorder (P = 0.0655);Loss of disorder (P = 0.0655);
MVP		0.82
MPC		0.26
ClinPred		0.68	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.46
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-46656145;