11-66347099-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_006876.3(B4GAT1):c.447G>C(p.Met149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,582,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

B4GAT1
NM_006876.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.32

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]

B4GAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031127453).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000118 (18/152240) while in subpopulation NFE AF= 0.000191 (13/68036). AF 95% confidence interval is 0.000112. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B4GAT1	NM_006876.3 linkuse as main transcript	c.447G>C	p.Met149Ile	missense_variant	1/2	ENST00000311181.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B4GAT1	ENST00000311181.5 linkuse as main transcript	c.447G>C	p.Met149Ile	missense_variant	1/2	1	NM_006876.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

209752

Hom.:

AF XY:

0.0000522

AC XY:

AN XY:

114924

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000203

AC:

290

AN:

1429782

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

144

AN XY:

708096

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:

0.000260

Gnomad4 OTH exome

AF:

0.0000848

GnomAD4 genome

AF:

0.000118

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000784

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000584

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.447G>C (p.M149I) alteration is located in exon 1 (coding exon 1) of the B4GAT1 gene. This alteration results from a G to C substitution at nucleotide position 447, causing the methionine (M) at amino acid position 149 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2021

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 149 of the B4GAT1 protein (p.Met149Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with B4GAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577279). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Benign

0.88

DEOGEN2

Benign

0.15

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.67

M_CAP

Benign

0.0055

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.91

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.6

REVEL

Benign

0.060

Sift

Benign

0.81

Sift4G

Benign

0.91

Polyphen

0.0

Vest4

0.12

MutPred

0.43

Loss of disorder (P = 0.0727);

MVP

0.014

MPC

0.92

ClinPred

0.043

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over