NM_012200.4:c.830G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong

The NM_012200.4(B3GAT3):c.830G>A(p.Arg277Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

B3GAT3
NM_012200.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.14

Publications

15 publications found

Variant links:

Genes affected

B3GAT3 (HGNC:923): (beta-1,3-glucuronyltransferase 3) The protein encoded by this gene is a member of the glucuronyltransferase gene family, enzymes that exhibit strict acceptor specificity, recognizing nonreducing terminal sugars and their anomeric linkages. This gene product catalyzes the formation of the glycosaminoglycan-protein linkage by way of a glucuronyl transfer reaction in the final step of the biosynthesis of the linkage region of proteoglycans. A pseudogene of this gene has been identified on chromosome 3. [provided by RefSeq, Dec 2013]

B3GAT3 Gene-Disease associations (from GenCC):

Larsen-like syndrome, B3GAT3 type
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

B3GAT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.69161 (below the threshold of 3.09). Trascript score misZ: 1.8273 (below the threshold of 3.09). GenCC associations: The gene is linked to Larsen-like syndrome, B3GAT3 type, complex neurodevelopmental disorder.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-62616585-C-T is Pathogenic according to our data. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62616585-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GAT3	NM_012200.4 link	c.830G>A	p.Arg277Gln	missense_variant	Exon 4 of 5	ENST00000265471.10	NP_036332.2	O94766-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B3GAT3	ENST00000265471.10 link	c.830G>A	p.Arg277Gln	missense_variant	Exon 4 of 5	1	NM_012200.4	ENSP00000265471.5		O94766-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251250

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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.:

Alfa

AF:

0.0000150

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Larsen-like syndrome, B3GAT3 type

Pathogenic:2

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in a 5-year-old male with global delays, short stature, skeletal abnormalities, broad thumbs and halluces, joing laxity, bilateral hip dysplasia, multiple dental caries, generalized cortical atrophy, dilation of aortic root and pulmonary artery, inguinal hernia. -

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects B3GAT3 function (PMID: 21763480). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30573). This missense change has been observed in individual(s) with multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects (PMID: 21763480). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387906937, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 277 of the B3GAT3 protein (p.Arg277Gln). -

not provided

Pathogenic:1

Jun 04, 2015

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM3,PS3,PM2,PP3,PP1 -

MULTIPLE JOINT DISLOCATIONS, SHORT STATURE, AND CRANIOFACIAL DYSMORPHISM WITH CONGENITAL HEART DEFECTS

Pathogenic:1

Jun 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.9

L;.;L

PhyloP100

4.1

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.026

D;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.98

D;.;.

Vest4

0.73

MutPred

0.53

Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);

MVP

0.82

MPC

0.71

ClinPred

0.72

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.70

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over