11-373220-G-C

Variant names:

• chr11-373220-G-C
• NM_178537.5:c.565G>C

Variant summary

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

The NM_178537.5(B4GALNT4):​c.565G>C​(p.Asp189His) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: B4GALNT4 NM_178537.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22
• Publications: 0 publications found

Genes affected

B4GALNT4 (HGNC:26315): (beta-1,4-N-acetyl-galactosaminyltransferase 4) Enables acetylgalactosaminyltransferase activity. Predicted to be located in Golgi cisterna membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALNT4	NM_178537.5	c.565G>C	p.Asp189His	missense_variant	Exon 6 of 20	ENST00000329962.11	NP_848632.2
B4GALNT4	XM_017017654.2	c.289G>C	p.Asp97His	missense_variant	Exon 6 of 20		XP_016873143.1
B4GALNT4	XR_001747858.2	n.870G>C		non_coding_transcript_exon_variant	Exon 6 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALNT4	ENST00000329962.11	c.565G>C	p.Asp189His	missense_variant	Exon 6 of 20	1	NM_178537.5	ENSP00000328277.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.565G>C (p.D189H) alteration is located in exon 6 (coding exon 6) of the B4GALNT4 gene. This alteration results from a G to C substitution at nucleotide position 565, causing the aspartic acid (D) at amino acid position 189 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.75		Gain of catalytic residue at N190 (P = 0.0436);
MVP		0.47
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.96
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr11-373220;