rs715930

Variant names:

• chr12-57630198-C-A
• rs715930
• NM_001478.5:c.666G>T
• B4GALNT1 p.Leu222Leu

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001413981.1(B4GALNT1):​c.-322G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,614,046 control chromosomes in the GnomAD database, including 37,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3977 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33825 hom.)
• Consequence: B4GALNT1 NM_001413981.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63
• Publications: 38 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), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-57630198-C-A is Benign according to our data. Variant chr12-57630198-C-A is described in ClinVar as Benign. ClinVar VariationId is 380770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413981.1. 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.666G>T	p.Leu222Leu	synonymous	Exon 6 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413981.1		c.-322G>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 12	NP_001400910.1
	B4GALNT1	NM_001413982.1		c.-322G>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 12	NP_001400911.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	ENST00000341156.9	TSL:1 MANE Select	c.666G>T	p.Leu222Leu	synonymous	Exon 6 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000550764.5	TSL:1	c.666G>T	p.Leu222Leu	synonymous	Exon 6 of 6	ENSP00000450303.1	Q00973-3
	B4GALNT1	ENST00000882412.1		c.666G>T	p.Leu222Leu	synonymous	Exon 6 of 11	ENSP00000552471.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33923 AN: 152064 Hom.: 3971 Cov.: 33

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.213 AC: 53492 AN: 251354 AF XY: 0.203

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.211 AC: 308489 AN: 1461864 Hom.: 33825 Cov.: 35 AF XY: 0.207 AC XY: 150469 AN XY: 727232

African (AFR) AF: 0.279 AC: 9351 AN: 33480

American (AMR) AF: 0.324 AC: 14505 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3229 AN: 26136

East Asian (EAS) AF: 0.114 AC: 4512 AN: 39700

South Asian (SAS) AF: 0.143 AC: 12305 AN: 86254

European-Finnish (FIN) AF: 0.207 AC: 11033 AN: 53420

Middle Eastern (MID) AF: 0.108 AC: 622 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241033 AN: 1111994

Other (OTH) AF: 0.197 AC: 11899 AN: 60392

GnomAD4 genome AF: 0.223 AC: 33964 AN: 152182 Hom.: 3977 Cov.: 33 AF XY: 0.220 AC XY: 16359 AN XY: 74414

African (AFR) AF: 0.269 AC: 11165 AN: 41506

American (AMR) AF: 0.267 AC: 4080 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3472

East Asian (EAS) AF: 0.130 AC: 671 AN: 5172

South Asian (SAS) AF: 0.153 AC: 739 AN: 4826

European-Finnish (FIN) AF: 0.201 AC: 2130 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14198 AN: 68002

Other (OTH) AF: 0.198 AC: 417 AN: 2110

Alfa AF: 0.209 Hom.: 7021

Bravo AF: 0.232

Asia WGS AF: 0.145 AC: 507 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.191

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.29
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs715930;

hg19: chr12-58023981;

COSMIC: COSV57542001;

COSMIC: COSV57542001;