11-66346179-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006876.3(B4GAT1):​c.1118A>T​(p.His373Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

B4GAT1
NM_006876.3 missense

Scores

13
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69
Variant links:
Genes affected
B4GAT1 (HGNC:15685): (beta-1,4-glucuronyltransferase 1) This gene encodes a member of the beta-1,3-N-acetylglucosaminyltransferase family. This enzyme is a type II transmembrane protein. It is essential for the synthesis of poly-N-acetyllactosamine, a determinant for the blood group i antigen. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
B4GAT1NM_006876.3 linkuse as main transcriptc.1118A>T p.His373Leu missense_variant 2/2 ENST00000311181.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
B4GAT1ENST00000311181.5 linkuse as main transcriptc.1118A>T p.His373Leu missense_variant 2/21 NM_006876.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461870
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 19, 2022This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 disruptive. This variant has not been reported in the literature in individuals affected with B4GAT1-related conditions. This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 373 of the B4GAT1 protein (p.His373Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
32
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.90
D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.74
T
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.33
D
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-11
D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.90
MutPred
0.77
Loss of disorder (P = 0.061);
MVP
0.57
MPC
2.1
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.93
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.29
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.29
Position offset: -5

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: chr11-66113650; API