Genetic Variant NM_178537.5:c.146G>A (chr11-369949-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_178537.5(B4GALNT4):c.146G>A(p.Gly49Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 975,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G49R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

B4GALNT4
NM_178537.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

Publications

0 publications found

Variant links:

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]

B4GALNT4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28539303).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALNT4	NM_178537.5 link	c.146G>A	p.Gly49Glu	missense_variant	Exon 1 of 20	ENST00000329962.11	NP_848632.2	Q76KP1
B4GALNT4	XR_001747858.2 link	n.451G>A		non_coding_transcript_exon_variant	Exon 1 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALNT4	ENST00000329962.11 link	c.146G>A	p.Gly49Glu	missense_variant	Exon 1 of 20	1	NM_178537.5	ENSP00000328277.6		Q76KP1
B4GALNT4	ENST00000530717.1 link	n.154G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000282

AC:

AN:

142060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000621

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

833118

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

384846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15762

American (AMR)

AF:

0.00

AC:

AN:

1008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5168

East Asian (EAS)

AF:

0.00

AC:

AN:

3714

South Asian (SAS)

AF:

0.00

AC:

AN:

17276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1624

European-Non Finnish (NFE)

AF:

0.0000105

AC:

AN:

760952

Other (OTH)

AF:

0.0000733

AC:

AN:

27280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000282

AC:

AN:

142060

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

68884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39466

American (AMR)

AF:

0.00

AC:

AN:

14420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3346

East Asian (EAS)

AF:

0.00

AC:

AN:

4898

South Asian (SAS)

AF:

0.00

AC:

AN:

4588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

64452

Other (OTH)

AF:

0.00

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.146G>A (p.G49E) alteration is located in exon 1 (coding exon 1) of the B4GALNT4 gene. This alteration results from a G to A substitution at nucleotide position 146, causing the glycine (G) at amino acid position 49 to be replaced by a glutamic acid (E). 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

Benign

0.19

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0084

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PhyloP100

3.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.087

Sift

Uncertain

0.020

Sift4G

Benign

0.23

Polyphen

0.96

Vest4

0.17

MutPred

0.41

Gain of solvent accessibility (P = 0.005);

MVP

0.068

MPC

1.1

ClinPred

0.84

GERP RS

2.0

PromoterAI

0.028

Neutral

(source)

Varity_R

0.41

gMVP

0.44

Mutation Taster

=68/32

polymorphism

(source)

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

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NM_178537.5:c.146G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over