12-57628835-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001478.5(B4GALNT1):c.880G>A(p.Ala294Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,216 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 12 hom. )

Consequence

B4GALNT1
NM_001478.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0120

Publications

4 publications found

Variant links:

Genes affected

B4GALNT1 (HGNC:4117): (beta-1,4-N-acetyl-galactosaminyltransferase 1) GM2 and GD2 gangliosides are sialic acid-containing glycosphingolipids. GalNAc-T is the enzyme involved in the biosynthesis of G(M2) and G(D2) glycosphingolipids. GalNAc-T catalyzes the transfer of GalNAc into G(M3) and G(D3) by a beta-1,4 linkage, resulting in the synthesis of G(M2) and G(D2), respectively. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

B4GALNT1 Gene-Disease associations (from GenCC):

complex hereditary spastic paraplegia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 26
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

B4GALNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006351173).

BP6

Variant 12-57628835-C-T is Benign according to our data. Variant chr12-57628835-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00146 (223/152322) while in subpopulation SAS AF = 0.00394 (19/4822). AF 95% confidence interval is 0.00258. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALNT1	NM_001478.5 link	c.880G>A	p.Ala294Thr	missense_variant	Exon 8 of 11	ENST00000341156.9	NP_001469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALNT1	ENST00000341156.9 link	c.880G>A	p.Ala294Thr	missense_variant	Exon 8 of 11	1	NM_001478.5	ENSP00000341562.4

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00182

AC:

457

AN:

251490

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00217

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00175

AC:

2553

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1281

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00219

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000932

AC:

AN:

39700

South Asian (SAS)

AF:

0.00350

AC:

302

AN:

86258

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00167

AC:

1852

AN:

1112012

Other (OTH)

AF:

0.00371

AC:

224

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

164

328

491

655

819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152322

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000721

AC:

AN:

41582

American (AMR)

AF:

0.00235

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5174

South Asian (SAS)

AF:

0.00394

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

B4GALNT1: BP4 -

Spastic paraplegia

Benign:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

B4GALNT1-related disorder

Benign:1

Feb 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.20

T;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

PhyloP100

0.012

PrimateAI

Benign

0.28

PROVEAN

Benign

0.23

N;N;.

REVEL

Benign

0.016

Sift

Benign

0.73

T;T;.

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.15

MVP

0.46

MPC

0.19

ClinPred

0.00099

GERP RS

-2.7

PromoterAI

0.018

Neutral

(source)

Varity_R

0.031

gMVP

0.39

Mutation Taster

=96/4

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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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