rs144643461

Variant names:

• chr12-57628217-T-C
• rs144643461
• NM_001478.5:c.1048A>G

Variant summary

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

The NM_001478.5(B4GALNT1):​c.1048A>G​(p.Lys350Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,614,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: B4GALNT1 NM_001478.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.59
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

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.1048A>G	p.Lys350Glu	missense	Exon 9 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413967.1		c.1183A>G	p.Lys395Glu	missense	Exon 9 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.1183A>G	p.Lys395Glu	missense	Exon 9 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.1048A>G	p.Lys350Glu	missense	Exon 9 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000882412.1		c.1183A>G	p.Lys395Glu	missense	Exon 9 of 11	ENSP00000552471.1
	B4GALNT1	ENST00000954202.1		c.1048A>G	p.Lys350Glu	missense	Exon 8 of 10	ENSP00000624261.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 251460 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000353 AC: 516 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000367 AC XY: 267 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000411 AC: 457 AN: 1112012

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74522

African (AFR) AF: 0.0000481 AC: 2 AN: 41596

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000271 Hom.: 1

Bravo AF: 0.000246

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000818

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 26 (1)
-	1	-	not provided (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.79
MPC		1.5
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.72
gMVP		0.85
Mutation Taster		=37/63	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: rs144643461; hg19: chr12-58022000; COSMIC: COSV99049704; COSMIC: COSV99049704;