chr11-66346766-G-C

Variant names:

• chr11-66346766-G-C
• rs1319732212
• NM_006876.3:c.780C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006876.3(B4GAT1):​c.780C>G​(p.Phe260Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F260F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B4GAT1 NM_006876.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0370
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GAT1	NM_006876.3	c.780C>G	p.Phe260Leu	missense_variant	Exon 1 of 2	ENST00000311181.5	NP_006867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GAT1	ENST00000311181.5	c.780C>G	p.Phe260Leu	missense_variant	Exon 1 of 2	1	NM_006876.3	ENSP00000309096.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13 Uncertain:1

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 260 of the B4GAT1 protein (p.Phe260Leu). This variant is not present in population databases (gnomAD no frequency). 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: 1009820). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.54	T
PhyloP100		-0.037
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.87		Gain of MoRF binding (P = 0.1003);
MVP		0.23
MPC		2.1
ClinPred		0.99	D
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.95
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs1319732212; hg19: chr11-66114237;