Genetic Variant STT3B:p.Ser13Leu (chr3-31533036-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_178862.3(STT3B):c.38C>T(p.Ser13Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000348 in 1,435,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. S13W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

STT3B
NM_178862.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.59

Publications

0 publications found

Variant links:

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]

STT3B Gene-Disease associations (from GenCC):

STT3B-congenital disorder of glycosylation
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: G2P, PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

STT3B links:

ENSG00000288926 (HGNC:):

ENSG00000288926 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity STT3B_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-31533036-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1686968.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18132469).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178862.3. 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
	STT3B	NM_178862.3	MANE Select	c.38C>T	p.Ser13Leu	missense	Exon 1 of 16	NP_849193.1	Q8TCJ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STT3B	ENST00000295770.4	TSL:1 MANE Select	c.38C>T	p.Ser13Leu	missense	Exon 1 of 16	ENSP00000295770.2	Q8TCJ2
STT3B	ENST00000453168.5	TSL:1	n.399C>T		non_coding_transcript_exon	Exon 1 of 10
STT3B	ENST00000935233.1		c.38C>T	p.Ser13Leu	missense	Exon 1 of 16	ENSP00000605292.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000348

AC:

AN:

1435548

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

714158

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000334

AC:

AN:

29914

American (AMR)

AF:

0.00

AC:

AN:

43058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.00

AC:

AN:

35196

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100536

Other (OTH)

AF:

0.00

AC:

AN:

59280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000852049), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

3.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.66

REVEL

Benign

0.043

Sift

Uncertain

0.015

Sift4G

Uncertain

0.017

Polyphen

0.043

Vest4

0.18

MutPred

0.24

Gain of catalytic residue at S13 (P = 0.0021)

MVP

0.12

MPC

0.75

ClinPred

0.83

GERP RS

3.7

PromoterAI

-0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.29

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over