3-31533009-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_178862.3(STT3B):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,437,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: STT3B NM_178862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

STT3B (HGNC:30611): (STT3 oligosaccharyltransferase complex catalytic subunit B) The protein encoded by this gene is a catalytic subunit of a protein complex that transfers oligosaccharides onto asparagine residues. Defects in this gene are a cause of congenital disorder of glycosylation Ix (CDG1X). [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STT3B
• BP4: Computational evidence support a benign effect (MetaRNN=0.14554074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STT3B	NM_178862.3	c.11C>T	p.Pro4Leu	missense_variant	1/16	ENST00000295770.4
STT3B	XM_011533465.2	c.11C>T	p.Pro4Leu	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STT3B	ENST00000295770.4	c.11C>T	p.Pro4Leu	missense_variant	1/16	1	NM_178862.3	P1
STT3B	ENST00000453168.5	n.372C>T		non_coding_transcript_exon_variant	1/10	1
STT3B	ENST00000423527.5	n.38C>T		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1437292 Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 4 AN XY: 714932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

STT3B-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2020

This sequence change replaces proline with leucine at codon 4 of the STT3B protein (p.Pro4Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STT3B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Benign	0.087	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.20		Gain of glycosylation at S9 (P = 0.0162);
MVP		0.14
MPC		0.87
ClinPred		0.65	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs1250170448; hg19: chr3-31574501;