NM_001478.5:c.880G>A

Variant names:

• chr12-57628835-C-T
• rs147301375
• NM_001478.5:c.880G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0120
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001478.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	NM_001478.5	MANE Select	c.880G>A	p.Ala294Thr	missense	Exon 8 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413967.1		c.880G>A	p.Ala294Thr	missense	Exon 8 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.880G>A	p.Ala294Thr	missense	Exon 8 of 11	NP_001400897.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	ENST00000341156.9	TSL:1 MANE Select	c.880G>A	p.Ala294Thr	missense	Exon 8 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000882412.1		c.880G>A	p.Ala294Thr	missense	Exon 8 of 11	ENSP00000552471.1
	B4GALNT1	ENST00000954202.1		c.880G>A	p.Ala294Thr	missense	Exon 7 of 10	ENSP00000624261.1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152204 Hom.: 0 Cov.: 33

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

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.: 12 Cov.: 32 AF XY: 0.00176 AC XY: 1281 AN XY: 727248

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39700

South Asian (SAS) AF: 0.00350 AC: 302 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00167 AC: 1852 AN: 1112012

Other (OTH) AF: 0.00371 AC: 224 AN: 60396

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74484

African (AFR) AF: 0.000721 AC: 30 AN: 41582

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00184 Hom.: 8

Bravo AF: 0.00138

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.0250 AC: 85 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	B4GALNT1-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.012
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.016
Sift	Benign	0.73	T
Sift4G	Benign	0.60	T
Polyphen		0.0020	B
Vest4		0.15
MVP		0.46
MPC		0.19
ClinPred		0.00099	T
GERP RS		-2.7
PromoterAI		0.018	Neutral
Varity_R		0.031
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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: rs147301375; hg19: chr12-58022618;